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Škrlec I, Biloglav Z, Lešić D, Talapko J, Žabić I, Katalinić D. Association of MTNR1B Gene Polymorphisms with Body Mass Index in Hashimoto's Thyroiditis. Int J Mol Sci 2025; 26:3667. [PMID: 40332199 PMCID: PMC12027080 DOI: 10.3390/ijms26083667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/02/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
Hashimoto's thyroiditis (HT) is an autoimmune disorder of the thyroid gland characterized by chronic inflammation, which in most cases results in hypothyroidism. The melatonin receptor MTNR1B is sporadically expressed in the thyroid gland. It modulates immune responses, and alterations in the melatonin-MTNR1B receptor signaling pathway may play a role in developing autoimmune diseases. Obesity worsens the severity and progression of some autoimmune diseases and reduces treatment efficacy. This study aimed to investigate the association of MTNR1B gene polymorphisms (rs10830963, rs1387153, and rs4753426) with HT with regards to the body mass index (BMI). Patients with HT were categorized into normal weight BMI ≤ 25 kg/m2 and overweight/obese BMI > 25 kg/m2 groups. This study included 115 patients with a clinical-, ultrasound-, and laboratory-confirmed diagnosis of HT (64 normal-weight patients and 51 overweight/obese patients) with a mean age of 43 ± 12 years. The results showed that specific MTNR1B polymorphisms are associated with obesity in HT patients. BMI was found to be associated with the rs10830963 polymorphism, and the G allele and GG genotype of the rs10830963 polymorphism were more common in overweight/obese HT patients. Furthermore, the results suggest that genetic factors associated with BMI play a role in developing HT and open new possibilities for personalized treatment approaches.
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Affiliation(s)
- Ivana Škrlec
- Faculty of Dental Medicine and Health, University J. J. Strossmayer Osijek, 31000 Osijek, Croatia
| | - Zrinka Biloglav
- Department of Medical Statistics, Epidemiology and Medical Informatics, School of Public Health Andrija Štampar, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Jasminka Talapko
- Faculty of Dental Medicine and Health, University J. J. Strossmayer Osijek, 31000 Osijek, Croatia
| | - Igor Žabić
- County Hospital Koprivnica, 48000 Koprivnica, Croatia
| | - Darko Katalinić
- Faculty of Dental Medicine and Health, University J. J. Strossmayer Osijek, 31000 Osijek, Croatia
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
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Udino E, Pessato A, Addison B, Crino OL, Buchanan KL, Mariette MM. Prenatal Acoustic Signals Influence Nestling Heat Shock Protein Response to Heat and Heterophil-to-Lymphocyte Ratio in a Desert Bird. Int J Mol Sci 2024; 25:12194. [PMID: 39596260 PMCID: PMC11595141 DOI: 10.3390/ijms252212194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Heat shock proteins (HSPs) are essential to cellular protection against heat stress. However, the causes of inter-individual variation in HSP regulation remain unclear. This study aimed to test the impact of early-life conditions on the HSP response to heat in zebra finches. In this arid-adapted bird, incubating parents emit "heat-calls" at high temperatures, which adaptively alter offspring's phenotypes. Embryos were exposed to heat-calls or control-calls, and at 13 days post-hatch nestlings were separated into two different experiments to test responses to either chronic nest temperature ("in-nest" experiment) or an acute "heat-challenge". Blood samples were collected to measure levels of heat shock cognate 70, heat shock protein 90α, corticosterone and the heterophil-to-lymphocyte (H/L) ratio. In the in-nest experiment, both HSPs were upregulated in response to increasing nest temperatures only in control-calls nestlings (HSC70: p = 0.010, HSP90α: p = 0.050), which also had a marginally higher H/L ratio overall than heat-call birds (p = 0.066). These results point to a higher heat sensitivity in control-call nestlings. Furthermore, comparing across experiments, only the H/L ratio differed, being higher in heat-challenged than in in-nest nestlings (p = 0.009). Overall, this study shows for the first time that a prenatal acoustic signal of heat affects the nestling HSP response to postnatal temperature.
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Affiliation(s)
- Eve Udino
- School of Life & Environmental Sciences, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Max Planck Institute for Biological Intelligence, Eberhard-Gwinner-Straße, 82319 Seewiesen, Germany
| | - Anaïs Pessato
- School of Life & Environmental Sciences, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Centre d’Écologie et des Sciences de la Conservation (CESCO), Muséum National d’Histoire Naturelle, Centre National de la Recherche Scientifique, Sorbonne Université, CP 135, 57 rue Cuvier, 75005 Paris, France
| | - BriAnne Addison
- School of Life & Environmental Sciences, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
| | - Ondi L. Crino
- School of Life & Environmental Sciences, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- College of Science and Engineering, Flinders University, Adelaide, SA 5042, Australia
| | - Katherine L. Buchanan
- School of Life & Environmental Sciences, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
| | - Mylene M. Mariette
- School of Life & Environmental Sciences, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Doñana Biological Station EBC-CSIC, Calle Américo-Vespucio 26, 41092 Sevilla, Spain
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Foyzun T, Whiting M, Velasco KK, Jacobsen JC, Connor M, Grimsey NL. Single nucleotide polymorphisms in the cannabinoid CB 2 receptor: Molecular pharmacology and disease associations. Br J Pharmacol 2024; 181:2391-2412. [PMID: 38802979 DOI: 10.1111/bph.16383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/26/2024] [Accepted: 03/09/2024] [Indexed: 05/29/2024] Open
Abstract
Preclinical evidence implicating cannabinoid receptor 2 (CB2) in various diseases has led researchers to question whether CB2 genetics influence aetiology or progression. Associations between conditions and genetic loci are often studied via single nucleotide polymorphism (SNP) prevalence in case versus control populations. In the CNR2 coding exon, ~36 SNPs have high overall population prevalence (minor allele frequencies [MAF] ~37%), including non-synonymous SNP (ns-SNP) rs2501432 encoding CB2 63Q/R. Interspersed are ~27 lower frequency SNPs, four being ns-SNPs. CNR2 introns also harbour numerous SNPs. This review summarises CB2 ns-SNP molecular pharmacology and evaluates evidence from ~70 studies investigating CB2 genetic variants with proposed linkage to disease. Although CNR2 genetic variation has been associated with a wide variety of conditions, including osteoporosis, immune-related disorders, and mental illnesses, further work is required to robustly validate CNR2 disease links and clarify specific mechanisms linking CNR2 genetic variation to disease pathophysiology and potential drug responses.
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Affiliation(s)
- Tahira Foyzun
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, New South Wales, Australia
| | - Maddie Whiting
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Kate K Velasco
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Jessie C Jacobsen
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
- Centre for Brain Research, University of Auckland, Auckland, New Zealand
| | - Mark Connor
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, New South Wales, Australia
| | - Natasha L Grimsey
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Centre for Brain Research, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
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Kuffler L, Skelly DA, Czechanski A, Fortin HJ, Munger SC, Baker CL, Reinholdt LG, Carter GW. Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice. eLife 2024; 12:RP88222. [PMID: 38669177 PMCID: PMC11052574 DOI: 10.7554/elife.88222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2024] Open
Abstract
Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these interactions have previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here, we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF-binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of 3D chromatin structure.
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Everman ER, Macdonald SJ. Gene expression variation underlying tissue-specific responses to copper stress in Drosophila melanogaster. G3 (BETHESDA, MD.) 2024; 14:jkae015. [PMID: 38262701 PMCID: PMC11021028 DOI: 10.1093/g3journal/jkae015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/25/2024]
Abstract
Copper is one of a handful of biologically necessary heavy metals that is also a common environmental pollutant. Under normal conditions, copper ions are required for many key physiological processes. However, in excess, copper results in cell and tissue damage ranging in severity from temporary injury to permanent neurological damage. Because of its biological relevance, and because many conserved copper-responsive genes respond to nonessential heavy metal pollutants, copper resistance in Drosophila melanogaster is a useful model system with which to investigate the genetic control of the heavy metal stress response. Because heavy metal toxicity has the potential to differently impact specific tissues, we genetically characterized the control of the gene expression response to copper stress in a tissue-specific manner in this study. We assessed the copper stress response in head and gut tissue of 96 inbred strains from the Drosophila Synthetic Population Resource using a combination of differential expression analysis and expression quantitative trait locus mapping. Differential expression analysis revealed clear patterns of tissue-specific expression. Tissue and treatment specific responses to copper stress were also detected using expression quantitative trait locus mapping. Expression quantitative trait locus associated with MtnA, Mdr49, Mdr50, and Sod3 exhibited both genotype-by-tissue and genotype-by-treatment effects on gene expression under copper stress, illuminating tissue- and treatment-specific patterns of gene expression control. Together, our data build a nuanced description of the roles and interactions between allelic and expression variation in copper-responsive genes, provide valuable insight into the genomic architecture of susceptibility to metal toxicity, and highlight candidate genes for future functional characterization.
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Affiliation(s)
- Elizabeth R Everman
- School of Biological Sciences, The University of Oklahoma, 730 Van Vleet Oval, Norman, OK 73019, USA
| | - Stuart J Macdonald
- Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave, Lawrence, KS 66045, USA
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Akgöllü E, Demirkazık M, Bilgin R. The effect of HLA-DP gene polymorphisms in Plasmodium Vivax-induced malaria susceptibility. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 43:572-584. [PMID: 37980631 DOI: 10.1080/15257770.2023.2283620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 11/08/2023] [Indexed: 11/21/2023]
Abstract
Plasmodium vivax is the second most common Plasmodium parasite causing clinically serious symptoms and death from malaria. It is an important cause of morbidity and mortality, especially in Asia, the Middle East, and South America. Human leukocyte antigen molecules are responsible for presenting foreign antigens to T cells. Polymorphisms in HLA genes affect antigen presentation. HLA alleles involved in the presentation of P. vivax antigens affect the antibody response. The present study aimed to reveal the relationship of rs3077 and rs9277535 polymorphisms in HLA-DP genes with malaria caused by P. vivax for the first time in the worldwide. In the present research, rs3077 and rs9277535 polymorphisms were investigated in a case-control study of 124 patients with P. vivax-induced malaria and 211 healthy persons by using a real-time polymerase chain reaction (RT-PCR). The results showed that the G alleles of rs3077 and rs9277535 polymorphisms were detected as protective alleles, while the A alleles of both polymorphisms increase the risk of susceptibility to malaria disease. The results of the present study showed that both polymorphisms have a major effect on the susceptibility to malaria caused by P. vivax. We recommend that this study should be conducted in a different population with a larger sample size to confirm our results.
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Affiliation(s)
- Ersin Akgöllü
- Patnos Vocational School, Department of Pharmacy, Ağrı İbrahim Çeçen University, Merkez/Ağrı, Turkey
| | - Mehtap Demirkazık
- Faculty of Medicine, Department of Parasitology, Çukurova University, Adana, Turkey
| | - Ramazan Bilgin
- Faculty of Science, Department of Chemistry, Çukurova University, Adana, Turkey
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Batista-Liz JC, Calvo-Río V, Sebastián Mora-Gil M, Sevilla-Pérez B, Márquez A, Leonardo MT, Peñalba A, Carmona FD, Narvaez J, Martín-Penagos L, Belmar-Vega L, Gómez-Fernández C, Caminal-Montero L, Collado P, Quiroga-Colina P, Uriarte-Ecenarro M, Rubio E, Luque ML, Blanco-Madrigal JM, Galíndez-Agirregoikoa E, Martín J, Castañeda S, González-Gay MA, Blanco R, Pulito-Cueto V, López-Mejías R. Mucosal Immune Defence Gene Polymorphisms as Relevant Players in the Pathogenesis of IgA Vasculitis? Int J Mol Sci 2023; 24:13063. [PMID: 37685869 PMCID: PMC10488110 DOI: 10.3390/ijms241713063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
ITGAM-ITGAX (rs11150612, rs11574637), VAV3 rs17019602, CARD9 rs4077515, DEFA (rs2738048, rs10086568), and HORMAD2 rs2412971 are mucosal immune defence polymorphisms, that have an impact on IgA production, described as risk loci for IgA nephropathy (IgAN). Since IgAN and Immunoglobulin-A vasculitis (IgAV) share molecular mechanisms, with the aberrant deposit of IgA1 being the main pathophysiologic feature of both entities, we assessed the potential influence of the seven abovementioned polymorphisms on IgAV pathogenesis. These seven variants were genotyped in 381 Caucasian IgAV patients and 997 matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of these seven polymorphisms when the whole cohort of IgAV patients and those with nephritis were compared to controls. Similar genotype and allele frequencies of all polymorphisms were disclosed when IgAV patients were stratified according to the age at disease onset or the presence/absence of gastrointestinal or renal manifestations. Likewise, no ITGAM-ITGAX and DEFA haplotype differences were observed when the whole cohort of IgAV patients, along with those with nephritis and controls, as well as IgAV patients, stratified according to the abovementioned clinical characteristics, were compared. Our results suggest that mucosal immune defence polymorphisms do not represent novel genetic risk factors for IgAV pathogenesis.
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Affiliation(s)
- Joao Carlos Batista-Liz
- Immunopathology Group, Rheumatology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, 39011 Santander, Spain; (J.C.B.-L.); (V.C.-R.); (M.S.M.-G.); (R.B.)
| | - Vanesa Calvo-Río
- Immunopathology Group, Rheumatology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, 39011 Santander, Spain; (J.C.B.-L.); (V.C.-R.); (M.S.M.-G.); (R.B.)
| | - María Sebastián Mora-Gil
- Immunopathology Group, Rheumatology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, 39011 Santander, Spain; (J.C.B.-L.); (V.C.-R.); (M.S.M.-G.); (R.B.)
| | - Belén Sevilla-Pérez
- Division of Paediatrics, Hospital Universitario San Cecilio, 18016 Granada, Spain;
| | - Ana Márquez
- Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, PTS Granada, 18016 Granada, Spain; (A.M.); (J.M.)
| | - María Teresa Leonardo
- Division of Paediatrics, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain; (M.T.L.); (A.P.)
| | - Ana Peñalba
- Division of Paediatrics, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain; (M.T.L.); (A.P.)
| | - Francisco David Carmona
- Departamento de Genética e Instituto de Biotecnología, Centro de Investigación Biomédica (CIBM), Universidad de Granada, 18071 Granada, Spain;
- Instituto de Investigación Biosanitaria ibs. Granada, 18012 Granada, Spain
| | - Javier Narvaez
- Division of Rheumatology, Hospital Universitario de Bellvitge, 08907 Barcelona, Spain;
| | - Luis Martín-Penagos
- Immunopathology Group, Division of Nephrology, Hospital Universitario Marqués de Valdecilla-IDIVAL, 39011 Santander, Spain; (L.M.-P.); (L.B.-V.)
| | - Lara Belmar-Vega
- Immunopathology Group, Division of Nephrology, Hospital Universitario Marqués de Valdecilla-IDIVAL, 39011 Santander, Spain; (L.M.-P.); (L.B.-V.)
| | | | - Luis Caminal-Montero
- Internal Medicine Department, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain;
| | - Paz Collado
- Division of Rheumatology, Hospital Universitario Severo Ochoa, 28911 Madrid, Spain;
| | - Patricia Quiroga-Colina
- Division of Rheumatology, Hospital Universitario de La Princesa, IIS-Princesa, 28006 Madrid, Spain; (P.Q.-C.); (M.U.-E.); (S.C.)
| | - Miren Uriarte-Ecenarro
- Division of Rheumatology, Hospital Universitario de La Princesa, IIS-Princesa, 28006 Madrid, Spain; (P.Q.-C.); (M.U.-E.); (S.C.)
| | - Esteban Rubio
- Department of Rheumatology, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain; (E.R.); (M.L.L.)
| | - Manuel León Luque
- Department of Rheumatology, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain; (E.R.); (M.L.L.)
| | - Juan María Blanco-Madrigal
- Division of Rheumatology, Hospital Universitario de Basurto, 48013 Bilbao, Spain; (J.M.B.-M.); (E.G.-A.)
| | - Eva Galíndez-Agirregoikoa
- Division of Rheumatology, Hospital Universitario de Basurto, 48013 Bilbao, Spain; (J.M.B.-M.); (E.G.-A.)
| | - Javier Martín
- Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, PTS Granada, 18016 Granada, Spain; (A.M.); (J.M.)
| | - Santos Castañeda
- Division of Rheumatology, Hospital Universitario de La Princesa, IIS-Princesa, 28006 Madrid, Spain; (P.Q.-C.); (M.U.-E.); (S.C.)
| | - Miguel Angel González-Gay
- Department of Rheumatology, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain;
- School of Medicine, Universidad de Cantabria, 39011 Santander, Spain
| | - Ricardo Blanco
- Immunopathology Group, Rheumatology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, 39011 Santander, Spain; (J.C.B.-L.); (V.C.-R.); (M.S.M.-G.); (R.B.)
| | - Verónica Pulito-Cueto
- Immunopathology Group, Rheumatology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, 39011 Santander, Spain; (J.C.B.-L.); (V.C.-R.); (M.S.M.-G.); (R.B.)
| | - Raquel López-Mejías
- Immunopathology Group, Rheumatology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, 39011 Santander, Spain; (J.C.B.-L.); (V.C.-R.); (M.S.M.-G.); (R.B.)
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Cuomo ASE, Nathan A, Raychaudhuri S, MacArthur DG, Powell JE. Single-cell genomics meets human genetics. Nat Rev Genet 2023; 24:535-549. [PMID: 37085594 PMCID: PMC10784789 DOI: 10.1038/s41576-023-00599-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/23/2023]
Abstract
Single-cell genomic technologies are revealing the cellular composition, identities and states in tissues at unprecedented resolution. They have now scaled to the point that it is possible to query samples at the population level, across thousands of individuals. Combining single-cell information with genotype data at this scale provides opportunities to link genetic variation to the cellular processes underpinning key aspects of human biology and disease. This strategy has potential implications for disease diagnosis, risk prediction and development of therapeutic solutions. But, effectively integrating large-scale single-cell genomic data, genetic variation and additional phenotypic data will require advances in data generation and analysis methods. As single-cell genetics begins to emerge as a field in its own right, we review its current state and the challenges and opportunities ahead.
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Affiliation(s)
- Anna S E Cuomo
- Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
- Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
- Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
| | - Aparna Nathan
- Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Divisions of Rheumatology and Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Soumya Raychaudhuri
- Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Divisions of Rheumatology and Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Daniel G MacArthur
- Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
- Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
| | - Joseph E Powell
- Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
- UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia.
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9
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Everman ER, Macdonald SJ. Gene expression variation underlying tissue-specific responses to copper stress in Drosophila melanogaster. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.12.548746. [PMID: 37503205 PMCID: PMC10370140 DOI: 10.1101/2023.07.12.548746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Copper is one of a handful of biologically necessary heavy metals that is also a common environmental pollutant. Under normal conditions, copper ions are required for many key physiological processes. However, in excess, copper quickly results in cell and tissue damage that can range in severity from temporary injury to permanent neurological damage. Because of its biological relevance, and because many conserved copper-responsive genes also respond to other non-essential heavy metal pollutants, copper resistance in Drosophila melanogaster is a useful model system with which to investigate the genetic control of the response to heavy metal stress. Because heavy metal toxicity has the potential to differently impact specific tissues, we genetically characterized the control of the gene expression response to copper stress in a tissue-specific manner in this study. We assessed the copper stress response in head and gut tissue of 96 inbred strains from the Drosophila Synthetic Population Resource (DSPR) using a combination of differential expression analysis and expression quantitative trait locus (eQTL) mapping. Differential expression analysis revealed clear patterns of tissue-specific expression, primarily driven by a more pronounced gene expression response in gut tissue. eQTL mapping of gene expression under control and copper conditions as well as for the change in gene expression following copper exposure (copper response eQTL) revealed hundreds of genes with tissue-specific local cis-eQTL and many distant trans-eQTL. eQTL associated with MtnA, Mdr49, Mdr50, and Sod3 exhibited genotype by environment effects on gene expression under copper stress, illuminating several tissue- and treatment-specific patterns of gene expression control. Together, our data build a nuanced description of the roles and interactions between allelic and expression variation in copper-responsive genes, provide valuable insight into the genomic architecture of susceptibility to metal toxicity, and highlight many candidate genes for future functional characterization.
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Affiliation(s)
- Elizabeth R Everman
- 1200 Sunnyside Ave, University of Kansas, Molecular Biosciences, Lawrence, KS 66045, USA
- 730 Van Vleet Oval, University of Oklahoma, Biology, Norman, OK 73019, USA
| | - Stuart J Macdonald
- 1200 Sunnyside Ave, University of Kansas, Molecular Biosciences, Lawrence, KS 66045, USA
- 1200 Sunnyside Ave, University of Kansas, Center for Computational Biology, Lawrence, KS 66045, USA
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10
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Frantz SI, Small CM, Cresko WA, Singh ND. Ovarian transcriptional response to Wolbachia infection in D. melanogaster in the context of between-genotype variation in gene expression. G3 (BETHESDA, MD.) 2023; 13:jkad047. [PMID: 36857313 PMCID: PMC10151400 DOI: 10.1093/g3journal/jkad047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 08/22/2022] [Accepted: 01/07/2023] [Indexed: 03/02/2023]
Abstract
Wolbachia is a maternally transmitted endosymbiotic bacteria that infects a wide variety of arthropod and nematode hosts. The effects of Wolbachia on host biology are far-reaching and include changes in host gene expression. However, previous work on the host transcriptional response has generally been investigated in the context of a single host genotype. Thus, the relative effect of Wolbachia infection versus vs. host genotype on gene expression is unknown. Here, we explicitly test the relative roles of Wolbachia infection and host genotype on host gene expression by comparing the ovarian transcriptomes of 4 strains of Drosophila melanogaster (D. melanogaster) infected and uninfected with Wolbachia. Our data suggest that infection explains a small amount of transcriptional variation, particularly in comparison to variation in gene expression among strains. However, infection specifically affects genes related to cell cycle, translation, and metabolism. We also find enrichment of cell division and recombination processes among genes with infection-associated differential expression. Broadly, the transcriptomic changes identified in this study provide novel understanding of the relative magnitude of the effect of Wolbachia infection on gene expression in the context of host genetic variation and also point to genes that are consistently differentially expressed in response to infection among multiple genotypes.
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Affiliation(s)
- Sophia I Frantz
- Institute of Ecology and Evolution, University of Oregon, Eugene, OR, 97403USA
| | - Clayton M Small
- Institute of Ecology and Evolution, University of Oregon, Eugene, OR, 97403USA
- Presidential Initiative in Data Science, University of Oregon, Eugene, OR, 97403USA
| | - William A Cresko
- Institute of Ecology and Evolution, University of Oregon, Eugene, OR, 97403USA
- Presidential Initiative in Data Science, University of Oregon, Eugene, OR, 97403USA
| | - Nadia D Singh
- Institute of Ecology and Evolution, University of Oregon, Eugene, OR, 97403USA
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11
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Pritchett EM, Van Goor A, Schneider BK, Young M, Lamont SJ, Schmidt CJ. Chicken pituitary transcriptomic responses to acute heat stress. Mol Biol Rep 2023; 50:5233-5246. [PMID: 37127810 DOI: 10.1007/s11033-023-08464-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 04/14/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND Poultry production is vulnerable to increasing temperatures in terms of animal welfare and in economic losses. With the predicted increase in global temperature and the number and severity of heat waves, it is important to understand how chickens raised for food respond to heat stress. This knowledge can be used to determine how to select chickens that are adapted to thermal challenge. As neuroendocrine organs, the hypothalamus and pituitary provide systemic regulation of the heat stress response. METHODS AND RESULTS Here we report a transcriptome analysis of the pituitary response to acute heat stress. Chickens were stressed for 2 h at 35 °C (HS) and transcriptomes compared with birds maintained in thermoneutral temperatures (25 °C). CONCLUSIONS The observations were evaluated in the context of ontology terms and pathways to describe the pituitary response to heat stress. The pituitaries of heat stressed birds exhibited responses to hyperthermia through altered expression of genes coding for chaperones, cell cycle regulators, cholesterol synthesis, transcription factors, along with the secreted peptide hormones, prolactin, and proopiomelanocortin.
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Affiliation(s)
| | - Angelica Van Goor
- Animal Science, Iowa State University, Ames, IA, USA
- Food Science and Human Nutrition, Iowa State University, Ames, IA, USA
| | | | - Meaghan Young
- Animal and Food Science, University of Delaware, Newark, DE, USA
| | | | - Carl J Schmidt
- Animal and Food Science, University of Delaware, Newark, DE, USA.
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12
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Liu S, Yao T, Chen D, Xiao S, Chen L, Zhang Z. Genomic prediction in pigs using data from a commercial crossbred population: insights from the Duroc x (Landrace x Yorkshire) three-way crossbreeding system. Genet Sel Evol 2023; 55:21. [PMID: 36977978 PMCID: PMC10053053 DOI: 10.1186/s12711-023-00794-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND Genomic selection is widely applied for genetic improvement in livestock crossbreeding systems to select excellent nucleus purebred (PB) animals and to improve the performance of commercial crossbred (CB) animals. Most current predictions are based solely on PB performance. Our objective was to explore the potential application of genomic selection of PB animals using genotypes of CB animals with extreme phenotypes in a three-way crossbreeding system as the reference population. Using real genotyped PB as ancestors, we simulated the production of 100,000 pigs for a Duroc x (Landrace x Yorkshire) DLY crossbreeding system. The predictive performance of breeding values of PB animals for CB performance using genotypes and phenotypes of (1) PB animals, (2) DLY animals with extreme phenotypes, and (3) random DLY animals for traits of different heritabilities ([Formula: see text] = 0.1, 0.3, and 0.5) was compared across different reference population sizes (500 to 6500) and prediction models (genomic best linear unbiased prediction (GBLUP) and Bayesian sparse linear mixed model (BSLMM)). RESULTS Using a reference population consisting of CB animals with extreme phenotypes showed a definite predictive advantage for medium- and low-heritability traits and, in combination with the BSLMM model, significantly improved selection response for CB performance. For high-heritability traits, the predictive performance of a reference population of extreme CB phenotypes was comparable to that of PB phenotypes when the effect of the genetic correlation between PB and CB performance ([Formula: see text]) on the accuracy obtained with a PB reference population was considered, and the former could exceed the latter if the reference size was large enough. For the selection of the first and terminal sires in a three-way crossbreeding system, prediction using extreme CB phenotypes outperformed the use of PB phenotypes, while the optimal design of the reference group for the first dam depended on the percentage of individuals from the corresponding breed that the PB reference data comprised and on the heritability of the target trait. CONCLUSIONS A commercial crossbred population is promising for the design of the reference population for genomic prediction, and selective genotyping of CB animals with extreme phenotypes has the potential for maximizing genetic improvement for CB performance in the pig industry.
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Affiliation(s)
- Siyi Liu
- National Key Laboratory for Swine Genetics, Breeding and Production Technology, Jiangxi Agricultural University, Nanchang, 330045, China
| | - Tianxiong Yao
- National Key Laboratory for Swine Genetics, Breeding and Production Technology, Jiangxi Agricultural University, Nanchang, 330045, China
| | - Dong Chen
- National Key Laboratory for Swine Genetics, Breeding and Production Technology, Jiangxi Agricultural University, Nanchang, 330045, China
| | - Shijun Xiao
- National Key Laboratory for Swine Genetics, Breeding and Production Technology, Jiangxi Agricultural University, Nanchang, 330045, China
| | - Liqing Chen
- National Key Laboratory for Swine Genetics, Breeding and Production Technology, Jiangxi Agricultural University, Nanchang, 330045, China
| | - Zhiyan Zhang
- National Key Laboratory for Swine Genetics, Breeding and Production Technology, Jiangxi Agricultural University, Nanchang, 330045, China.
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13
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Huang Y, Luo J, Zhang Y, Zhang T, Fei X, Chen L, Zhu Y, Li S, Zhou C, Xu K, Ma Y, Lin J, Zhou J. Identification of MKNK1 and TOP3A as ovarian endometriosis risk-associated genes using integrative genomic analyses and functional experiments. Comput Struct Biotechnol J 2023; 21:1510-1522. [PMID: 36851918 PMCID: PMC9957794 DOI: 10.1016/j.csbj.2023.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 01/11/2023] [Accepted: 02/01/2023] [Indexed: 02/07/2023] Open
Abstract
The risk of endometriosis (EM), which is a common complex gynaecological disease, is related to genetic predisposition. However, it is unclear how genetic variants confer the risk of EM. Here, via Sherlock integrative analysis, we combined large-scale genome-wide association studies (GWAS) summary statistics on EM (N = 245,494) with a blood-based eQTL dataset (N = 1490) to identify EM risk-related genes. For validation, we leveraged two independent eQTL datasets (N = 769) for integration with the GWAS data. Thus, we prioritised 14 genes, including GIMAP4, TOP3A, and NMNAT3, which showed significant association with susceptibility to EM. We also utilised two independent methods, Multi-marker Analysis of GenoMic Annotation and S-PrediXcan, to further validate the EM risk-associated genes. Moreover, protein-protein interaction network analysis showed the 14 genes were functionally connected. Functional enrichment analyses further demonstrated that these genes were significantly enriched in metabolic and immune-related pathways. Differential gene expression analysis showed that in peripheral blood samples from patients with ovarian EM, TOP3A, MKNK1, SIPA1L2, and NUCB1 were significantly upregulated, while HOXB2, GIMAP5, and MGMT were significantly downregulated compared with their expression levels in samples from the controls. Immunohistochemistry further confirmed the increased expression levels of MKNK1 and TOP3A in the ectopic and eutopic endometrium compared to normal endometrium, while HOBX2 was downregulated in the endometrium of women with ovarian EM. Finally, in ex vivo functional experiments, MKNK1 knockdown inhibited ectopic endometrial stromal cells (EESCs) migration and invasion. TOP3A knockdown inhibited EESCs proliferation, migration, and invasion, while promoting their apoptosis. Convergent lines of evidence suggested that MKNK1 and TOP3A are novel EM risk-related genes.
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Affiliation(s)
- Yizhou Huang
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Jie Luo
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Yue Zhang
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Tao Zhang
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Xiangwei Fei
- Key Laboratory of Women's Reproductive Health of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Liqing Chen
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Yingfan Zhu
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Songyue Li
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Caiyun Zhou
- Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Kaihong Xu
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Yunlong Ma
- Institute of Biomedical Big Data, School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University 325027 Wenzhou, Zhejiang Province, PR China
| | - Jun Lin
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
| | - Jianhong Zhou
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, PR China
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Martin-Trujillo A, Garg P, Patel N, Jadhav B, Sharp AJ. Genome-wide evaluation of the effect of short tandem repeat variation on local DNA methylation. Genome Res 2023; 33:184-196. [PMID: 36577521 PMCID: PMC10069470 DOI: 10.1101/gr.277057.122] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 12/19/2022] [Indexed: 12/30/2022]
Abstract
Short tandem repeats (STRs) contribute significantly to genetic diversity in humans, including disease-causing variation. Although the effect of STR variation on gene expression has been extensively assessed, their impact on epigenetics has been poorly studied and limited to specific genomic regions. Here, we investigated the hypothesis that some STRs act as independent regulators of local DNA methylation in the human genome and modify risk of common human traits. To address these questions, we first analyzed two independent data sets comprising PCR-free whole-genome sequencing (WGS) and genome-wide DNA methylation levels derived from whole-blood samples in 245 (discovery cohort) and 484 individuals (replication cohort). Using genotypes for 131,635 polymorphic STRs derived from WGS using HipSTR, we identified 11,870 STRs that associated with DNA methylation levels (mSTRs) of 11,774 CpGs (Bonferroni P < 0.001) in our discovery cohort, with 90% successfully replicating in our second cohort. Subsequently, through fine-mapping using CAVIAR we defined 585 of these mSTRs as the likely causal variants underlying the observed associations (fm-mSTRs) and linked a fraction of these to previously reported genome-wide association study signals, providing insights into the mechanisms underlying complex human traits. Furthermore, by integrating gene expression data, we observed that 12.5% of the tested fm-mSTRs also modulate expression levels of nearby genes, reinforcing their regulatory potential. Overall, our findings expand the catalog of functional sequence variants that affect genome regulation, highlighting the importance of incorporating STRs in future genetic association analysis and epigenetics data for the interpretation of trait-associated variants.
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Affiliation(s)
- Alejandro Martin-Trujillo
- Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, New York 10029, USA
| | - Paras Garg
- Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, New York 10029, USA
| | - Nihir Patel
- Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, New York 10029, USA
| | - Bharati Jadhav
- Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, New York 10029, USA
| | - Andrew J Sharp
- Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, New York 10029, USA
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15
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Crespo-Piazuelo D, Acloque H, González-Rodríguez O, Mongellaz M, Mercat MJ, Bink MCAM, Huisman AE, Ramayo-Caldas Y, Sánchez JP, Ballester M. Identification of transcriptional regulatory variants in pig duodenum, liver, and muscle tissues. Gigascience 2022; 12:giad042. [PMID: 37354463 PMCID: PMC10290502 DOI: 10.1093/gigascience/giad042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 04/13/2023] [Accepted: 05/25/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND In humans and livestock species, genome-wide association studies (GWAS) have been applied to study the association between variants distributed across the genome and a phenotype of interest. To discover genetic polymorphisms affecting the duodenum, liver, and muscle transcriptomes of 300 pigs from 3 different breeds (Duroc, Landrace, and Large White), we performed expression GWAS between 25,315,878 polymorphisms and the expression of 13,891 genes in duodenum, 12,748 genes in liver, and 11,617 genes in muscle. RESULTS More than 9.68 × 1011 association tests were performed, yielding 14,096,080 significantly associated variants, which were grouped in 26,414 expression quantitative trait locus (eQTL) regions. Over 56% of the variants were within 1 Mb of their associated gene. In addition to the 100-kb region upstream of the transcription start site, we identified the importance of the 100-kb region downstream of the 3'UTR for gene regulation, as most of the cis-regulatory variants were located within these 2 regions. We also observed 39,874 hotspot regulatory polymorphisms associated with the expression of 10 or more genes that could modify the protein structure or the expression of a regulator gene. In addition, 2 motifs (5'-GATCCNGYGTTGCYG-3' and a poly(A) sequence) were enriched across the 3 tissues within the neighboring sequences of the most significant single-nucleotide polymorphisms in each cis-eQTL region. CONCLUSIONS The 14 million significant associations obtained in this study are publicly available and have enabled the identification of expression-associated cis-, trans-, and hotspot regulatory variants within and across tissues, thus shedding light on the molecular mechanisms of regulatory variations that shape end-trait phenotypes.
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Affiliation(s)
- Daniel Crespo-Piazuelo
- Animal Breeding and Genetics Program, IRTA, Torre Marimon, Caldes de Montbui (08140), Spain
| | - Hervé Acloque
- GABI, Université Paris-Saclay, INRAE, AgroParisTech, Jouy-en-Josas (78350), France
| | | | - Mayrone Mongellaz
- GABI, Université Paris-Saclay, INRAE, AgroParisTech, Jouy-en-Josas (78350), France
| | | | - Marco C A M Bink
- Hendrix Genetics Research Technology & Services B.V., Boxmeer (5830 AC), The Netherlands
| | | | - Yuliaxis Ramayo-Caldas
- Animal Breeding and Genetics Program, IRTA, Torre Marimon, Caldes de Montbui (08140), Spain
| | - Juan Pablo Sánchez
- Animal Breeding and Genetics Program, IRTA, Torre Marimon, Caldes de Montbui (08140), Spain
| | - Maria Ballester
- Animal Breeding and Genetics Program, IRTA, Torre Marimon, Caldes de Montbui (08140), Spain
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16
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Current challenges in understanding the role of enhancers in disease. Nat Struct Mol Biol 2022; 29:1148-1158. [PMID: 36482255 DOI: 10.1038/s41594-022-00896-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 11/04/2022] [Indexed: 12/13/2022]
Abstract
Enhancers play a central role in the spatiotemporal control of gene expression and tend to work in a cell-type-specific manner. In addition, they are suggested to be major contributors to phenotypic variation, evolution and disease. There is growing evidence that enhancer dysfunction due to genetic, structural or epigenetic mechanisms contributes to a broad range of human diseases referred to as enhanceropathies. Such mechanisms often underlie the susceptibility to common diseases, but can also play a direct causal role in cancer or Mendelian diseases. Despite the recent gain of insights into enhancer biology and function, we still have a limited ability to predict how enhancer dysfunction impacts gene expression. Here we discuss the major challenges that need to be overcome when studying the role of enhancers in disease etiology and highlight opportunities and directions for future studies, aiming to disentangle the molecular basis of enhanceropathies.
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17
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Rasooly D, Peloso GM, Giambartolomei C. Bayesian Genetic Colocalization Test of Two Traits Using coloc. Curr Protoc 2022; 2:e627. [PMID: 36515558 DOI: 10.1002/cpz1.627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Genetic colocalization is an approach for determining whether a genetic variant at a particular locus is shared across multiple phenotypes. Genome-wide association studies (GWAS) have successfully mapped genetic variants associated with thousands of complex traits and diseases. However, a large proportion of GWAS signals fall in non-coding regions of the genome, making functional interpretation a challenge. Colocalization relies on a Bayesian framework that can integrate summary statistics, for example those derived from GWAS and expression quantitative trait loci (eQTL) mapping, to assess whether two or more independent association signals at a region of interest are consistent with a shared causal variant. The results from a colocalization analysis may be used to evaluate putative causal relationships between omics-based molecular measurements and a complex disease, and can generate hypotheses that may be followed up by tailored experiments. In this article, we present an easy and straightforward protocol for conducting a Bayesian test for colocalization of two traits using the 'coloc' package in R with summary-level results derived from GWAS and eQTL studies. We also provide general guidelines that can assist in the interpretation of findings generated from colocalization analyses. © 2022 Wiley Periodicals LLC. Basic Protocol: Performing a genetic colocalization analysis using the 'coloc' package in R and summary-level data Support Protocol: Installing the 'coloc' R package.
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Affiliation(s)
- Danielle Rasooly
- Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Gina M Peloso
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
| | - Claudia Giambartolomei
- Non-Coding RNAs and RNA-Based Therapeutics, Istituto Italiano di Tecnologia, Via Morego, Genova, Italy
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18
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Lee S, Zhang Y, Newhams M, Novak T, Thomas PG, Mourani PM, Hall MW, Loftis LL, Cvijanovich NZ, Tarquinio KM, Schwarz AJ, Weiss SL, Thomas NJ, Markovitz B, Cullimore ML, Sanders RC, Zinter MS, Sullivan JE, Halasa NB, Bembea MM, Giuliano JS, Typpo KV, Nofziger RA, Shein SL, Kong M, Coates BM, Weiss ST, Lange C, Su HC, Randolph AG, for the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Pediatric Intensive Care Influenza (PICFlu) Investigators and the Trans-Omics for Precision Medicine (TOPMed) Investigators. DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents. J Infect Dis 2022; 226:2030-2036. [PMID: 35986912 PMCID: PMC10205622 DOI: 10.1093/infdis/jiac350] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/18/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Seasonal influenza virus infection causes a range of disease severity, including lower respiratory tract infection with respiratory failure. We evaluated the association of common variants in interferon (IFN) regulatory genes with susceptibility to critical influenza infection in children. METHODS We performed targeted sequencing of 69 influenza-associated candidate genes in 348 children from 24 US centers admitted to the intensive care unit with influenza infection and lacking risk factors for severe influenza infection (PICFlu cohort, 59.4% male). As controls, whole genome sequencing from 675 children with asthma (CAMP cohort, 62.5% male) was compared. We assessed functional relevance using PICFlu whole blood gene expression levels for the gene and calculated IFN gene signature score. RESULTS Common variants in DDX58, encoding the retinoic acid-inducible gene I (RIG-I) receptor, demonstrated association above or around the Bonferroni-corrected threshold (synonymous variant rs3205166; intronic variant rs4487862). The intronic single-nucleotide polymorphism rs4487862 minor allele was associated with decreased DDX58 expression and IFN signature (P < .05 and P = .0009, respectively) which provided evidence supporting the genetic variants' impact on RIG-I and IFN immunity. CONCLUSIONS We provide evidence associating common gene variants in DDX58 with susceptibility to severe influenza infection in children. RIG-I may be essential for preventing life-threatening influenza-associated disease.
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Affiliation(s)
- Sanghun Lee
- Department of Biostatistics, T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Department of Medical Consilience, Graduate School, Dankook University, Yongin-si, South Korea
| | - Yu Zhang
- Laboratory of Clinical Immunology and Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Margaret Newhams
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Tanya Novak
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Anesthesia, Harvard Medical School, Boston, Massachusetts, USA
| | - Paul G Thomas
- Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Peter M Mourani
- Section of Critical Care Medicine, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, Arkansas, USA
| | - Mark W Hall
- Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Laura L Loftis
- Section of Critical Care Medicine, Department of Pediatrics, Texas Children’s Hospital, Houston, Texas, USA
| | - Natalie Z Cvijanovich
- Division of Critical Care Medicine, UCSF Benioff Children’s Hospital Oakland, Oakland, California, USA
| | - Keiko M Tarquinio
- Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Adam J Schwarz
- Department of Pediatrics, Children’s Hospital of Orange County, Orange, California, USA
| | - Scott L Weiss
- Division of Critical Care, Department of Anesthesiology and Critical Care, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Neal J Thomas
- Department of Pediatrics, Penn State Hershey Children’s Hospital, Penn State University College of Medicine, Hershey, Pennsylvania, USA
| | - Barry Markovitz
- Department of Anesthesiology Critical Care Medicine, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | - Melissa L Cullimore
- Division of Pediatric Critical Care, Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Ronald C Sanders
- Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, Arkansas, USA
| | - Matt S Zinter
- Divisions of Critical Care Medicine and Allergy, Immunology, and Bone Marrow Transplant, Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA
| | - Janice E Sullivan
- Division of Pediatric Critical Care, University of Louisville School of Medicine and Norton Children’s Hospital, Louisville, Kentucky, USA
| | - Natasha B Halasa
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Melania M Bembea
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - John S Giuliano
- Division of Critical Care, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Katri V Typpo
- Department of Pediatrics, Steele Children’s Research Center, University of Arizona, Tucson, Arizona, USA
| | - Ryan A Nofziger
- Division of Critical Care Medicine, Department of Pediatrics, Akron Children’s Hospital, Akron, Ohio, USA
| | - Steven L Shein
- Division of Pediatric Critical Care Medicine, Rainbow Babies and Children’s Hospital, Cleveland, Ohio, USA
| | - Michele Kong
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Bria M Coates
- Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
| | - Scott T Weiss
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Christoph Lange
- Department of Biostatistics, T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Helen C Su
- Laboratory of Clinical Immunology and Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Adrienne G Randolph
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Anesthesia, Harvard Medical School, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
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Lezhnyova V, Davidyuk Y, Mullakhmetova A, Markelova M, Zakharov A, Khaiboullina S, Martynova E. Analysis of herpesvirus infection and genome single nucleotide polymorphism risk factors in multiple sclerosis, Volga federal district, Russia. Front Immunol 2022; 13:1010605. [PMID: 36451826 PMCID: PMC9703080 DOI: 10.3389/fimmu.2022.1010605] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/03/2022] [Indexed: 09/29/2023] Open
Abstract
Multiple sclerosis (MS) is a heterogeneous disease where herpesvirus infection and genetic predisposition are identified as the most consistent risk factors. Serum and blood samples were collected from 151 MS and 70 controls and used to analyze circulating antibodies for, and DNA of, Epstein Barr virus (EBV), human cytomegalovirus (HCMV), human herpes virus 6 (HHV6), and varicella zoster virus (VZV). The frequency of selected single nucleotide polymorphisms (SNPs) in MS and controls were studied. Herpesvirus DNA in blood samples were analyzed using qPCR. Anti-herpesvirus antibodies were detected by ELISA. SNPs were analyzed by the allele-specific PCR. For statistical analysis, Fisher exact test, odds ratio and Kruskall-Wallis test were used; p<0.05 values were considered as significant. We have found an association between circulating anti-HHV6 antibodies and MS diagnosis. We also confirmed higher frequency of A and C alleles in rs2300747 and rs12044852 of CD58 gene and G allele in rs929230 of CD6 gene in MS as compared to controls. Fatigue symptom was linked to AC and AA genotype in rs12044852 of CD58 gene. An interesting observation was finding higher frequency of GG genotype in rs12722489 of IL2RA and T allele in rs1535045 of CD40 genes in patient having anti-HHV6 antibodies. A link was found between having anti-VZV antibodies in MS and CC genotype in rs1883832 of CD40 gene.
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Affiliation(s)
- Vera Lezhnyova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia
| | - Yuriy Davidyuk
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia
| | - Asia Mullakhmetova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia
| | - Maria Markelova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia
| | - Alexander Zakharov
- Department of Neurology and Neurosurgery, Samara State Medical University, Samara, Russia
| | - Svetlana Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia
| | - Ekaterina Martynova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia
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20
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Washington C, Dapas M, Biddanda A, Magnaye KM, Aneas I, Helling BA, Szczesny B, Boorgula MP, Taub MA, Kenny E, Mathias RA, Barnes KC, Khurana Hershey GK, Kercsmar CM, Gereige JD, Makhija M, Gruchalla RS, Gill MA, Liu AH, Rastogi D, Busse W, Gergen PJ, Visness CM, Gold DR, Hartert T, Johnson CC, Lemanske RF, Martinez FD, Miller RL, Ownby D, Seroogy CM, Wright AL, Zoratti EM, Bacharier LB, Kattan M, O'Connor GT, Wood RA, Nobrega MA, Altman MC, Jackson DJ, Gern JE, McKennan CG, Ober C. African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans. Genome Med 2022; 14:112. [PMID: 36175932 PMCID: PMC9520885 DOI: 10.1186/s13073-022-01114-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 09/15/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. METHODS We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. RESULTS Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. CONCLUSIONS Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.
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Affiliation(s)
- Charles Washington
- Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA
| | - Matthew Dapas
- Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA
| | - Arjun Biddanda
- Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA
| | - Kevin M Magnaye
- Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA
| | - Ivy Aneas
- Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA
| | - Britney A Helling
- Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA
| | - Brooke Szczesny
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | | | - Margaret A Taub
- Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Eimear Kenny
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rasika A Mathias
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Kathleen C Barnes
- Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | | | - Carolyn M Kercsmar
- Division of Asthma Research, Cincinnati Children's Hospital, Cincinnati, OH, USA
| | - Jessica D Gereige
- Department of Medicine, Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Melanie Makhija
- Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | | | - Michelle A Gill
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Andrew H Liu
- Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA
| | - Deepa Rastogi
- Children's National Hospital and George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - William Busse
- University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | | | | | - Diane R Gold
- The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Tina Hartert
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Christine C Johnson
- Department of Public Health Sciences, Henry Ford Health Systems, Detroit, MI, USA
| | - Robert F Lemanske
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Fernando D Martinez
- Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA
| | - Rachel L Miller
- Department of Medicine, Division of Clinical Immunology Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dennis Ownby
- Department of Public Health Sciences, Henry Ford Health Systems, Detroit, MI, USA
| | - Christine M Seroogy
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Anne L Wright
- Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA
| | - Edward M Zoratti
- Department of Medicine, Henry Ford Health Systems, Detroit, MI, USA
| | - Leonard B Bacharier
- Department of Pediatrics, Monroe Carell Jr Children's Hospital at Vanderbilt University Medical Center, Nashville, TN, USA
| | - Meyer Kattan
- Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
| | - George T O'Connor
- Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
| | - Robert A Wood
- Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
| | - Marcelo A Nobrega
- Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA
| | - Matthew C Altman
- Immunology Division, Benaroya Research Institute Systems, Seattle, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Daniel J Jackson
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - James E Gern
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | | | - Carole Ober
- Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA.
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21
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Bankier S, Michoel T. eQTLs as causal instruments for the reconstruction of hormone linked gene networks. Front Endocrinol (Lausanne) 2022; 13:949061. [PMID: 36060942 PMCID: PMC9428692 DOI: 10.3389/fendo.2022.949061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
Hormones act within in highly dynamic systems and much of the phenotypic response to variation in hormone levels is mediated by changes in gene expression. The increase in the number and power of large genetic association studies has led to the identification of hormone linked genetic variants. However, the biological mechanisms underpinning the majority of these loci are poorly understood. The advent of affordable, high throughput next generation sequencing and readily available transcriptomic databases has shown that many of these genetic variants also associate with variation in gene expression levels as expression Quantitative Trait Loci (eQTLs). In addition to further dissecting complex genetic variation, eQTLs have been applied as tools for causal inference. Many hormone networks are driven by transcription factors, and many of these genes can be linked to eQTLs. In this mini-review, we demonstrate how causal inference and gene networks can be used to describe the impact of hormone linked genetic variation upon the transcriptome within an endocrinology context.
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Affiliation(s)
- Sean Bankier
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
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22
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Senabouth A, Daniszewski M, Lidgerwood GE, Liang HH, Hernández D, Mirzaei M, Keenan SN, Zhang R, Han X, Neavin D, Rooney L, Lopez Sanchez MIG, Gulluyan L, Paulo JA, Clarke L, Kearns LS, Gnanasambandapillai V, Chan CL, Nguyen U, Steinmann AM, McCloy RA, Farbehi N, Gupta VK, Mackey DA, Bylsma G, Verma N, MacGregor S, Watt MJ, Guymer RH, Powell JE, Hewitt AW, Pébay A. Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration. Nat Commun 2022; 13:4233. [PMID: 35882847 PMCID: PMC9325891 DOI: 10.1038/s41467-022-31707-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 06/29/2022] [Indexed: 11/08/2022] Open
Abstract
There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.
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Affiliation(s)
- Anne Senabouth
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Maciej Daniszewski
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia
| | - Grace E Lidgerwood
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia
| | - Helena H Liang
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia
| | - Damián Hernández
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia
| | - Mehdi Mirzaei
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Stacey N Keenan
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Ran Zhang
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Xikun Han
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Drew Neavin
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Louise Rooney
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | | | - Lerna Gulluyan
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Linda Clarke
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia
| | - Lisa S Kearns
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia
| | | | - Chia-Ling Chan
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Uyen Nguyen
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Angela M Steinmann
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Rachael A McCloy
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Nona Farbehi
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Vivek K Gupta
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - David A Mackey
- Lions Eye Institute, Centre for Vision Sciences, University of Western Australia, Perth, WA, 6009, Australia
- School of Medicine, University of Tasmania, Hobart, TAS, 7005, Australia
| | - Guy Bylsma
- Lions Eye Institute, Centre for Vision Sciences, University of Western Australia, Perth, WA, 6009, Australia
| | - Nitin Verma
- School of Medicine, University of Tasmania, Hobart, TAS, 7005, Australia
| | - Stuart MacGregor
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Matthew J Watt
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Robyn H Guymer
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia
- Department of Surgery, Ophthalmology, Royal Victorian Eye and Ear Hospital, The University of Melbourne, East Melbourne, VIC, 3002, Australia
| | - Joseph E Powell
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.
- UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW, 2052, Australia.
| | - Alex W Hewitt
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia.
- School of Medicine, University of Tasmania, Hobart, TAS, 7005, Australia.
- Department of Surgery, Ophthalmology, Royal Victorian Eye and Ear Hospital, The University of Melbourne, East Melbourne, VIC, 3002, Australia.
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia.
| | - Alice Pébay
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia.
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia.
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3010, Australia.
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23
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Jiang X, Yang Z, Wang S, Deng S. “Big Data” Approaches for Prevention of the Metabolic Syndrome. Front Genet 2022; 13:810152. [PMID: 35571045 PMCID: PMC9095427 DOI: 10.3389/fgene.2022.810152] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 03/28/2022] [Indexed: 11/21/2022] Open
Abstract
Metabolic syndrome (MetS) is characterized by the concurrence of multiple metabolic disorders resulting in the increased risk of a variety of diseases related to disrupted metabolism homeostasis. The prevalence of MetS has reached a pandemic level worldwide. In recent years, extensive amount of data have been generated throughout the research targeted or related to the condition with techniques including high-throughput screening and artificial intelligence, and with these “big data”, the prevention of MetS could be pushed to an earlier stage with different data source, data mining tools and analytic tools at different levels. In this review we briefly summarize the recent advances in the study of “big data” applications in the three-level disease prevention for MetS, and illustrate how these technologies could contribute tobetter preventive strategies.
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Affiliation(s)
- Xinping Jiang
- Department of United Ultrasound, The First Hospital of Jilin University, Changchun, China
| | - Zhang Yang
- Department of Vascular Surgery, The First Hospital of Jilin University, Changchun, China
| | - Shuai Wang
- Department of Vascular Surgery, The First Hospital of Jilin University, Changchun, China
| | - Shuanglin Deng
- Department of Oncological Neurosurgery, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Shuanglin Deng,
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24
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Mai Q, He D, Zou H. Coordinatewise Gaussianization: Theories and Applications. J Am Stat Assoc 2022. [DOI: 10.1080/01621459.2022.2044825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Qing Mai
- Department of Statistics, Florida State University
| | - Di He
- School of Economics, Nanjing University, Nanjing, 210046, China
| | - Hui Zou
- School of Statistics, University of Minnesota
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25
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Teruel M, Barturen G, Martínez-Bueno M, Castellini-Pérez O, Barroso-Gil M, Povedano E, Kerick M, Català-Moll F, Makowska Z, Buttgereit A, Pers JO, Marañón C, Ballestar E, Martin J, Carnero-Montoro E, Alarcón-Riquelme ME. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature. Sci Rep 2021; 11:23292. [PMID: 34857786 PMCID: PMC8640069 DOI: 10.1038/s41598-021-01324-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 10/19/2021] [Indexed: 12/24/2022] Open
Abstract
Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.
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Affiliation(s)
- María Teruel
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain
| | - Guillermo Barturen
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain
| | - Manuel Martínez-Bueno
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain
| | - Olivia Castellini-Pérez
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain
| | - Miguel Barroso-Gil
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain
| | - Elena Povedano
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain
| | - Martin Kerick
- IPBLN-CSIC, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, 18016, Granada, Spain
| | - Francesc Català-Moll
- Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 08916, Badalona, Barcelona, Spain
- IDIBELL, Bellvitge Biomedical Research Institute 08907 L'Hospitalet de Llobregat, Barcelona, Spain
| | - Zuzanna Makowska
- Pharmaceuticals Division, Bayer Pharma Aktiengesellschaft, Berlin, Germany
| | - Anne Buttgereit
- Pharmaceuticals Division, Bayer Pharma Aktiengesellschaft, Berlin, Germany
| | | | - Concepción Marañón
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain
| | - Esteban Ballestar
- Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 08916, Badalona, Barcelona, Spain
- IDIBELL, Bellvitge Biomedical Research Institute 08907 L'Hospitalet de Llobregat, Barcelona, Spain
| | - Javier Martin
- IPBLN-CSIC, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, 18016, Granada, Spain
| | - Elena Carnero-Montoro
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain.
| | - Marta E Alarcón-Riquelme
- GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain.
- Institute for Environmental Medicine, Karolinska Institutet, 171 67, Solna, Sweden.
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26
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Keane JT, Afrasiabi A, Schibeci SD, Fewings N, Parnell GP, Swaminathan S, Booth DR. Gender and the Sex Hormone Estradiol Affect Multiple Sclerosis Risk Gene Expression in Epstein-Barr Virus-Infected B Cells. Front Immunol 2021; 12:732694. [PMID: 34566997 PMCID: PMC8455923 DOI: 10.3389/fimmu.2021.732694] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/23/2021] [Indexed: 12/04/2022] Open
Abstract
Multiple Sclerosis (MS) is a complex immune-mediated disease of the central nervous system. Treatment is based on immunomodulation, including specifically targeting B cells. B cells are the main host for the Epstein-Barr Virus (EBV), which has been described as necessary for MS development. Over 200 genetic loci have been identified as increasing susceptibility to MS. Many MS risk genes have altered expression in EBV infected B cells, dependent on the risk genotype, and are themselves regulated by the EBV transcription factor EBNA2. Females are 2-3 times more likely to develop MS than males. We investigated if MS risk loci might mediate the gender imbalance in MS. From a large public dataset, we identified gender-specific associations with EBV traits, and MS risk SNP/gene pairs with gender differences in their associations with gene expression. Some of these genes also showed gender differences in correlation of gene expression level with Estrogen Receptor 2. To test if estrogens may drive these gender specific differences, we cultured EBV infected B cells (lymphoblastoid cell lines, LCLs), in medium depleted of serum to remove the effects of sex hormones as well as the estrogenic effect of phenol red, and then supplemented with estrogen (100 nM estradiol). Estradiol treatment altered MS risk gene expression, LCL proliferation rate, EBV DNA copy number and EBNA2 expression in a sex-dependent manner. Together, these data indicate that there are estrogen-mediated gender-specific differences in MS risk gene expression and EBV functions. This may in turn contribute to gender differences in host response to EBV and to MS susceptibility.
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Affiliation(s)
- Jeremy T. Keane
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Ali Afrasiabi
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
- BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW SYDNEY, Sydney, NSW, Australia
| | - Stephen D. Schibeci
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Nicole Fewings
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Grant P. Parnell
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Sanjay Swaminathan
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
- Department of Medicine, Western Sydney University, Sydney, NSW, Australia
| | - David R. Booth
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
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Lin D, Chen J, Duan K, Perrone-Bizzozero N, Sui J, Calhoun V, Liu J. Network modules linking expression and methylation in prefrontal cortex of schizophrenia. Epigenetics 2021; 16:876-893. [PMID: 33079616 PMCID: PMC8331039 DOI: 10.1080/15592294.2020.1827718] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/13/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023] Open
Abstract
Tremendous work has demonstrated the critical roles of genetics, epigenetics as well as their interplay in brain transcriptional regulations in the pathology of schizophrenia (SZ). There is great success currently in the dissection of the genetic components underlying risk-conferring transcriptomic networks. However, the study of regulating effect of epigenetics in the etiopathogenesis of SZ still faces many challenges. In this work, we investigated DNA methylation and gene expression from the dorsolateral prefrontal cortex (DLPFC) region of schizophrenia patients and healthy controls using weighted correlation network approach. We identified and replicated two expression and two methylation modules significantly associated with SZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were significantly enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expression-methylation module pairs were involved ageing process with module genes mostly related to oligodendrocyte development and myelination, and specifically expressed in oligodendrocytes. Further examination of underlying quantitative trait loci (QTLs) showed significant enrichment in genetic risk of most psychiatric disorders for expression QTLs but not for methylation QTLs. These results support the coherence between methylation and gene expression at the network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation to SZ and ageing process.
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Affiliation(s)
- Dongdong Lin
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA
| | - Jiayu Chen
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA
| | - Kuaikuai Duan
- Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, USA
| | - Nora Perrone-Bizzozero
- Department of Neurosciences, University of New Mexico, Albuquerque, NM, USA
- Department of Psychiatry, University of New Mexico, Albuquerque, NM, USA
| | - Jing Sui
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA
| | - Vince Calhoun
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA
- Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, USA
- Department of Psychology, Georgia State University, Atlanta, USA
- Department of Computer Science, Georgia State University, Atlanta, USA
| | - Jingyu Liu
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA
- Department of Computer Science, Georgia State University, Atlanta, USA
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28
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Sun C, Wang S, Zhang Y, Yang F, Zeng T, Meng F, Yang M, Yang Y, Hua Y, Fu Z, Li J, Huang X, Wu H, Yin Y, Li W. Risk Signature of Cancer-Associated Fibroblast-Secreted Cytokines Associates With Clinical Outcomes of Breast Cancer. Front Oncol 2021; 11:628677. [PMID: 34395236 PMCID: PMC8356635 DOI: 10.3389/fonc.2021.628677] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 06/16/2021] [Indexed: 11/18/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are key components in tumor microenvironment (TME). The secreted products of CAFs play important roles in regulating tumor cells and further impacting clinical prognosis. This study aims to reveal the relationship between CAF-secreted cytokines and breast cancer (BC) by constructing the risk signature. We performed three algorithms to reveal CAF-related cytokines in the TCGA BC dataset and identified five prognosis-related cytokines. Then we used single-cell RNA sequencing (ScRNA-Seq) datasets of BC to confirm the expression level of these five cytokines in CAFs. METABRIC and other independent datasets were utilized to validate the findings in further analyses. Based on the identified five-cytokine signature derived from CAFs, BC patients with high-risk score (RS) had shorter overall survival than low-RS cases. Further analysis suggested that the high-RS level correlated with cell proliferation and mast cell infiltration in BCs of the Basal-like subtype. The results also indicated that the level of RS could discriminate the high-risk BC cases harboring driver mutations (i.e., PI3KCA, CDH1, and TP53). Additionally, the status of five-cytokine signature was associated with the frequency and molecular timing of whole genome duplication (WGD) events. Intratumor heterogeneity (ITH) analysis among BC samples indicated that the high-RS level was associated with the increase of tumor subclones. This work demonstrated that the prognostic signature based on CAF-secreted cytokines was associated with clinical outcome, tumor progression, and genetic alteration. Our findings may provide insights to develop novel strategies for early intervention and prognostic prediction of BC.
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Affiliation(s)
- Chunxiao Sun
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Siwei Wang
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Yuchen Zhang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fan Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tianyu Zeng
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fanchen Meng
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Mengzhu Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yiqi Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yijia Hua
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ziyi Fu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiang Huang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Wu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Wei Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Oncology, Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
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29
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Dabbou S, Lauwaerts A, Ferrocino I, Biasato I, Sirri F, Zampiga M, Bergagna S, Pagliasso G, Gariglio M, Colombino E, Narro CG, Gai F, Capucchio MT, Gasco L, Cocolin L, Schiavone A. Modified Black Soldier Fly Larva Fat in Broiler Diet: Effects on Performance, Carcass Traits, Blood Parameters, Histomorphological Features and Gut Microbiota. Animals (Basel) 2021; 11:ani11061837. [PMID: 34205603 PMCID: PMC8233813 DOI: 10.3390/ani11061837] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/08/2021] [Accepted: 06/14/2021] [Indexed: 11/29/2022] Open
Abstract
Simple Summary Black soldier fly (Hermetia illucens L.; BSF) is gaining interest as a functional feed additive, due to the high amount of medium-chain fatty acids (MCFAs) and monoglycerides, which provide antimicrobial activities and stimulate gastrointestinal health through inhibition of potentially pathogenic bacteria. The present study evaluated the effect of BSF and modified BSF larvae fat in broiler chicken’s diet. Overall results were comparable among the studied diets, suggesting that modified BSF larvae fat showed a positive modulation of fecal microbiota by a positive reduction in potentially pathogenic bacteria such as Clostridium and Corynebacterium, without affecting intestinal morphology or showing any adverse histopathological alternations. Abstract In this study, a total of 200 male broiler chickens (Ross 308) were assigned to four dietary treatments (5 pens/treatment and 10 birds/pen) for two feeding phases: starter (0–11 days of age) and grower-finisher (11–33 days of age). A basal diet containing soy oil (SO) as added fat was used as control group (C), tested against three experimental diets where the SO was partially substituted by BSF larvae fat (BSF) or one of two types of modified BSF larvae fat (MBSF1 and MBSF2, respectively). The two modified BSF larvae fats had a high and low ratio of monobutyrin to monoglycerides of medium chain fatty acid, respectively. Diet did not influence the growth or slaughter performance, pH, color, or the chemical composition of breast and thigh muscles, gut morphometric indices, or histopathological alterations in all the organs. As far as fecal microbiota are concerned, MBSF1 and MBSF2 diets reduced the presence of Clostridium and Corynebacterium, which can frequently cause infection in poultry. In conclusion, modified BSF larva fat may positively modulate the fecal microbiota of broiler chickens without influencing the growth performance and intestinal morphology or showing any adverse histopathological alternations.
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Affiliation(s)
- Sihem Dabbou
- Center Agriculture Food Environment (C3A), University of Trento, Via E. Mach 1, 38010 San Michele all’Adige, Italy;
| | | | - Ilario Ferrocino
- Department of Agricultural, Forest and Food Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy; (I.B.); (L.G.); (L.C.)
- Correspondence:
| | - Ilaria Biasato
- Department of Agricultural, Forest and Food Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy; (I.B.); (L.G.); (L.C.)
| | - Federico Sirri
- Department of Agricultural and Food Sciences, Alma Mater Studiorum—University of Bologna, Via del Florio 2, Ozzano dell’Emilia, 40064 Bologna, Italy; (F.S.); (M.Z.)
| | - Marco Zampiga
- Department of Agricultural and Food Sciences, Alma Mater Studiorum—University of Bologna, Via del Florio 2, Ozzano dell’Emilia, 40064 Bologna, Italy; (F.S.); (M.Z.)
| | - Stefania Bergagna
- Veterinary Medical Research Institute for Piemonte, Liguria and Valle d’Aosta, Via Bologna 148, 10154 Turin, Italy; (S.B.); (G.P.)
| | - Giulia Pagliasso
- Veterinary Medical Research Institute for Piemonte, Liguria and Valle d’Aosta, Via Bologna 148, 10154 Turin, Italy; (S.B.); (G.P.)
| | - Marta Gariglio
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy; (M.G.); (E.C.); (M.T.C.); (A.S.)
| | - Elena Colombino
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy; (M.G.); (E.C.); (M.T.C.); (A.S.)
| | - Carlos Garcés Narro
- Faculty of Veterinary Medicine, Universidad CEU Cardenal Herrera, CEU Universities, Alfara de Patriarca, E-46115 Valencia, Spain;
| | - Francesco Gai
- Institute of Science of Food Production, National Research Council, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy;
| | - Maria Teresa Capucchio
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy; (M.G.); (E.C.); (M.T.C.); (A.S.)
| | - Laura Gasco
- Department of Agricultural, Forest and Food Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy; (I.B.); (L.G.); (L.C.)
| | - Luca Cocolin
- Department of Agricultural, Forest and Food Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy; (I.B.); (L.G.); (L.C.)
| | - Achille Schiavone
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, 10095 Turin, Italy; (M.G.); (E.C.); (M.T.C.); (A.S.)
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30
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Tang LL, Meng Z, Li Q. A ROC-based test for evaluating the group difference with an application to neonatal audiology screening. Stat Med 2021; 40:4597-4608. [PMID: 34050680 DOI: 10.1002/sim.9082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 11/09/2022]
Abstract
This article proposes a powerful method to compare two samples. The proposed method handles comparison of data by drawing inference from ROC curve model parameters. The method estimates parameters from a linear model framework on the empirical sensitivities and specificities. The consistent ROC parameters are then used to give a more powerful test than existing methods in several situations. In addition, we present a comprehensive statistic based on the Cauchy combination, which works well in all scenarios considered in this article. We also offer an efficient one-layer wild permutation procedure to calculate the P-value of our statistic. The method is particularly useful when the underlying continuous biomarker results are non-normal. We illustrate the proposed methods in a neonatal audiology diagnostic example.
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Affiliation(s)
- Larry L Tang
- Department of Statistics, National Center for Forensic Science, University of Central Florida, Orlando, Florida.,Rehabilitation Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland
| | - Zhen Meng
- School of Statistics, Capital University of Economics and Business, Beijing, China
| | - Qizhai Li
- LSC, NCMIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.,School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing, China
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31
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Hamashita Y, Shibata T, Takeuchi A, Okuno T, Kise N, Sakurai T. Inchworm-type PNA-PEG conjugate regulates gene expression based on single nucleotide recognition. Int J Biol Macromol 2021; 181:471-477. [PMID: 33798568 DOI: 10.1016/j.ijbiomac.2021.03.140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 03/23/2021] [Indexed: 10/21/2022]
Abstract
In order to detect single nucleotide mutations and suppress gene expression, we synthesized an artificial nucleic acid, an inchworm-type PNA-PEG conjugate (i-PPc), that possessed a chemical structure in which 8 residues of peptide nucleic acid (PNA) were linked to both ends of a polyethylene glycol molecule. I-PPc_T7FM, which forms a complementary strand with the T7 promoter region of luciferase-expressing mRNA, failed to suppress the amount of luciferase produced via gene expression. However, 10 μM of i-PPc_ATGFM, targeting the start codon of luciferase (Luc+), suppressed approximately 85% of Luc+ production compared to that of the control in the cell-free protein synthesis system. Moreover, i-PPc_ATGMM (i-PPc_ATGFM with a single base mutation) only suppressed the amount of luciferase produced by approximately 15%, and such suppression of luciferase expression has not been achieved with block-type PPc or PNA oligos. The thermodynamic parameters suggested that the difference in stability of each PNA segment of the i-PPc contributed to single nucleotide recognition. These results indicate that the i-PPc could be used in antisense therapy to target single nucleotide polymorphisms (SNP).
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Affiliation(s)
- Yusuke Hamashita
- Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8552, Japan
| | - Takahiro Shibata
- Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8552, Japan
| | - Akiko Takeuchi
- Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8552, Japan
| | - Takashi Okuno
- Faculty of Science, Yamagata University, 1-4-12 Kojirakawa, Yamagata, 990-8560, Japan
| | - Naoki Kise
- Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8552, Japan; Center for Research on Green Sustainable Chemistry, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8552, Japan
| | - Toshihiko Sakurai
- Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8552, Japan; Center for Research on Green Sustainable Chemistry, Tottori University, 4-101 Koyama-Cho Minami, Tottori 680-8552, Japan.
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32
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Macauda A, Piredda C, Clay-Gilmour AI, Sainz J, Buda G, Markiewicz M, Barington T, Ziv E, Hildebrandt MAT, Belachew AA, Varkonyi J, Prejzner W, Druzd-Sitek A, Spinelli J, Andersen NF, Hofmann JN, Dudziński M, Martinez-Lopez J, Iskierka-Jazdzewska E, Milne RL, Mazur G, Giles GG, Ebbesen LH, Rymko M, Jamroziak K, Subocz E, Reis RM, Garcia-Sanz R, Suska A, Haastrup EK, Zawirska D, Grzasko N, Vangsted AJ, Dumontet C, Kruszewski M, Dutka M, Camp NJ, Waller RG, Tomczak W, Pelosini M, Raźny M, Marques H, Abildgaard N, Wątek M, Jurczyszyn A, Brown EE, Berndt S, Butrym A, Vachon CM, Norman AD, Slager SL, Gemignani F, Canzian F, Campa D. Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients. Int J Cancer 2021; 149:327-336. [PMID: 33675538 DOI: 10.1002/ijc.33547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 11/30/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022]
Abstract
Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.
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Affiliation(s)
- Angelica Macauda
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Biology, University of Pisa, Pisa, Italy
| | | | - Alyssa I Clay-Gilmour
- Department of Epidemiology & Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, USA
| | - Juan Sainz
- Genomic Oncology Area, GENYO. Centre for Genomics and Oncological Research: Pfizer, University of Granada/Andalusian Regional Government, Granada, Spain.,Hematology department, Virgen de las Nieves University Hospital, Granada, Spain
| | - Gabriele Buda
- Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Miroslaw Markiewicz
- Department of Hematology and Bone Marrow Transplantation, SPSKM Hospital, Katowice, Poland
| | - Torben Barington
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
| | - Elad Ziv
- Department of Medicine, Division of General Internal Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA
| | - Michelle A T Hildebrandt
- Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Alem A Belachew
- Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Judit Varkonyi
- Third Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Witold Prejzner
- Department of Hematology and Transplantation, Medical University of Gdansk, Gdansk, Poland
| | - Agnieszka Druzd-Sitek
- Department of Lymphoid Malignacies, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - John Spinelli
- Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Jonathan N Hofmann
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Marek Dudziński
- Department of Hematology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, Rzeszow, Poland
| | | | | | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.,Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.,Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Grzegorz Mazur
- Department of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.,Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.,Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | | | - Marcin Rymko
- Department of Hematology, N. Copernicus Town Hospital, Torun, Poland
| | - Krzysztof Jamroziak
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Edyta Subocz
- Department of Haematology, Military Institute of Medicine, Warsaw, Poland
| | - Rui Manuel Reis
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,Molecular Oncology Research Center, Barretos, São Paulo, Brazil
| | - Ramon Garcia-Sanz
- Department of Hematology, University Hospital of Salamanca, IBSAL, Salamanca, Spain
| | - Anna Suska
- Department of Hematology, Jagiellonian University Medical College, Cracow, Poland
| | - Eva Kannik Haastrup
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Daria Zawirska
- Department of Hematology, University Hospital of Cracow, Cracow, Poland
| | - Norbert Grzasko
- Department of Experimental Hematooncolog, Medical University of Lublin, Lublin, Poland.,Department of Hematology, St. John's Cancer Center, Lublin, Poland
| | - Annette Juul Vangsted
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Charles Dumontet
- Cancer Research Center of Lyon/Hospices Civils de Lyon, Lyon, France
| | - Marcin Kruszewski
- Department of Hematology, University Hospital Bydgoszcz, Bydgoszcz, Poland
| | - Magdalena Dutka
- Department of Hematology and Transplantation, Medical University of Gdansk, Gdansk, Poland
| | | | | | | | - Matteo Pelosini
- Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy
| | - Małgorzata Raźny
- Department of Hematology, Rydygier Specialistic Hospital, Cracow, Poland
| | | | - Niels Abildgaard
- Department of Hematology, Odense University Hospital, Odense, Denmark
| | - Marzena Wątek
- Hematology Clinic, Holycross Cancer Center, Kielce, Poland
| | - Artur Jurczyszyn
- Department of Hematology, Jagiellonian University Medical College, Cracow, Poland
| | - Elizabeth E Brown
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sonja Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Aleksandra Butrym
- Department of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland
| | - Celine M Vachon
- Genetic Epidemiology and Risk Assessment Program, Mayo Clinic Comprehensive Cancer Center, and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Aaron D Norman
- Genetic Epidemiology and Risk Assessment Program, Mayo Clinic Comprehensive Cancer Center, and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Susan L Slager
- Genetic Epidemiology and Risk Assessment Program, Mayo Clinic Comprehensive Cancer Center, and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy
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33
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Zhong Y, Chen L, Li J, Yao Y, Liu Q, Niu K, Ma Y, Xu Y. Integration of summary data from GWAS and eQTL studies identified novel risk genes for coronary artery disease. Medicine (Baltimore) 2021; 100:e24769. [PMID: 33725943 PMCID: PMC7982177 DOI: 10.1097/md.0000000000024769] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 01/23/2021] [Indexed: 01/05/2023] Open
Abstract
Several genetic loci have been reported to be significantly associated with coronary artery disease (CAD) by multiple genome-wide association studies (GWAS). Nevertheless, the biological and functional effects of these genetic variants on CAD remain largely equivocal. In the current study, we performed an integrative genomics analysis by integrating large-scale GWAS data (N = 459,534) and 2 independent expression quantitative trait loci (eQTL) datasets (N = 1890) to determine whether CAD-associated risk single nucleotide polymorphisms (SNPs) exert regulatory effects on gene expression. By using Sherlock Bayesian, MAGMA gene-based, multidimensional scaling (MDS), functional enrichment, and in silico permutation analyses for independent technical and biological replications, we highlighted 4 susceptible genes (CHCHD1, TUBG1, LY6G6C, and MRPS17) associated with CAD risk. Based on the protein-protein interaction (PPI) network analysis, these 4 genes were found to interact with each other. We detected a remarkably altered co-expression pattern among these 4 genes between CAD patients and controls. In addition, 3 genes of CHCHD1 (P = .0013), TUBG1 (P = .004), and LY6G6C (P = .038) showed significantly different expressions between CAD patients and controls. Together, we provide evidence to support that these identified genes such as CHCHD1 and TUBG1 are indicative factors of CAD.
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Affiliation(s)
- Yigang Zhong
- Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine
| | | | - Jingjing Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou
| | - Yinghao Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou
| | - Qiang Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou
| | - Kaimeng Niu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou
| | - Yunlong Ma
- Institute of Biomedical Big Data, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yizhou Xu
- Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine
- Zhejiang Chinese Medical University
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Robins C, Liu Y, Fan W, Duong DM, Meigs J, Harerimana NV, Gerasimov ES, Dammer EB, Cutler DJ, Beach TG, Reiman EM, De Jager PL, Bennett DA, Lah JJ, Wingo AP, Levey AI, Seyfried NT, Wingo TS. Genetic control of the human brain proteome. Am J Hum Genet 2021; 108:400-410. [PMID: 33571421 PMCID: PMC8008492 DOI: 10.1016/j.ajhg.2021.01.012] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/19/2021] [Indexed: 12/30/2022] Open
Abstract
We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects' tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.
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Yang F, Gleason KJ, Wang J, Duan J, He X, Pierce BL, Chen LS. CCmed: Cross-condition mediation analysis for identifying replicable trans-associations mediated by cis-gene expression. Bioinformatics 2021; 37:2513-2520. [PMID: 33647928 PMCID: PMC8428610 DOI: 10.1093/bioinformatics/btab139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/25/2021] [Indexed: 11/14/2022] Open
Abstract
MOTIVATION Trans-acting expression quantitative trait loci (eQTLs) collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are often individually weak. A large proportion of genetic effects on distal genes are mediated through cisgene expression. Cis-association (between SNP and cis-gene) and gene-gene correlation conditional on SNP genotype could establish trans-association (between SNP and trans-gene). Both cis-association and gene-gene conditional correlation have effects shared across relevant tissues and conditions, and transassociations mediated by cis-gene expression also have effects shared across relevant conditions. RESULTS . We proposed a Cross-Condition Mediation analysis method (CCmed) for detecting cis-mediated trans-associations with replicable effects in relevant conditions/studies. CCmed integrates cis-association and gene-gene conditional correlation statistics from multiple tissues/studies. Motivated by the bimodal effect-sharing patterns of eQTLs, we proposed two variations of CCmed, CCmedmost and CCmedspec for detecting cross-tissue and tissue-specific trans-associations, respectively. We analyzed data of 13 brain tissues from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-mediated transassociations across brain tissues, many of which showed evidence of trans-association in two replication studies. We also identified trans-genes associated with schizophrenia loci in at least two brain tissues. AVAILABILITY AND IMPLEMENTATION CCmed software is available at http://github.com/kjgleason/CCmed. SUPPLEMENTARY INFORMATION Supplementary Material are available at Bioinformatics online.
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Affiliation(s)
- Fan Yang
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, 13001 E. 17th Place, Aurora, Colorado, 80045, USA
| | - Kevin J Gleason
- Department of Public Health Sciences, University of Chicago, 5841 South Maryland Ave MC2000, Chicago, IL, 60637, USA
| | - Jiebiao Wang
- Department of Biostatistics, University of Pittsburgh, 7135 Public Health, 130 DeSoto Street, Pittsburgh, PA, 15261, USA
| | - Jubao Duan
- Center for Psychiatric Genetics, NorthShore University HealthSystem, 1001 University Place, Evanston, IL, 60201, USA.,Department of Psychiatry and Behavioral Neuroscience, 5841 S Maryland Ave, Chicago MC3077, Chicago, IL, 60637, USA
| | - Xin He
- Heart Center, Turku University Hospital and University of Turku, Turku, Finland
| | - Brandon L Pierce
- Department of Public Health Sciences, University of Chicago, 5841 South Maryland Ave MC2000, Chicago, IL, 60637, USA.,Heart Center, Turku University Hospital and University of Turku, Turku, Finland
| | - Lin S Chen
- Department of Public Health Sciences, University of Chicago, 5841 South Maryland Ave MC2000, Chicago, IL, 60637, USA
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36
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Yuan Z, Sunduimijid B, Xiang R, Behrendt R, Knight MI, Mason BA, Reich CM, Prowse-Wilkins C, Vander Jagt CJ, Chamberlain AJ, MacLeod IM, Li F, Yue X, Daetwyler HD. Expression quantitative trait loci in sheep liver and muscle contribute to variations in meat traits. Genet Sel Evol 2021; 53:8. [PMID: 33461502 PMCID: PMC7812657 DOI: 10.1186/s12711-021-00602-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 01/08/2021] [Indexed: 11/10/2022] Open
Abstract
Background Variants that regulate transcription, such as expression quantitative trait loci (eQTL), have shown enrichment in genome-wide association studies (GWAS) for mammalian complex traits. However, no study has reported eQTL in sheep, although it is an important agricultural species for which many GWAS of complex meat traits have been conducted. Using RNA sequence data produced from liver and muscle from 149 sheep and imputed whole-genome single nucleotide polymorphisms (SNPs), our aim was to dissect the genetic architecture of the transcriptome by associating sheep genotypes with three major molecular phenotypes including gene expression (geQTL), exon expression (eeQTL) and RNA splicing (sQTL). We also examined these three types of eQTL for their enrichment in GWAS of multi-meat traits and fatty acid profiles. Results Whereas a relatively small number of molecular phenotypes were significantly heritable (h2 > 0, P < 0.05), their mean heritability ranged from 0.67 to 0.73 for liver and from 0.71 to 0.77 for muscle. Association analysis between molecular phenotypes and SNPs within ± 1 Mb identified many significant cis-eQTL (false discovery rate, FDR < 0.01). The median distance between the eQTL and transcription start sites (TSS) ranged from 68 to 153 kb across the three eQTL types. The number of common variants between geQTL, eeQTL and sQTL within each tissue, and the number of common variants between liver and muscle within each eQTL type were all significantly (P < 0.05) larger than expected by chance. The identified eQTL were significantly (P < 0.05) enriched in GWAS hits associated with 56 carcass traits and fatty acid profiles. For example, several geQTL in muscle mapped to the FAM184B gene, hundreds of sQTL in liver and muscle mapped to the CAST gene, and hundreds of sQTL in liver mapped to the C6 gene. These three genes are associated with body composition or fatty acid profiles. Conclusions We detected a large number of significant eQTL and found that the overlap of variants between eQTL types and tissues was prevalent. Many eQTL were also QTL for meat traits. Our study fills a gap in the knowledge on the regulatory variants and their role in complex traits for the sheep model.
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Affiliation(s)
- Zehu Yuan
- State Key Laboratory of Grassland Agro-ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Grassland Agriculture Engineering Center, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, 730020, People's Republic of China.,Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia.,Institutes of Agricultural Science and Technology Development (Joint International Research Laboratory of Agriculture & Agri-Product Safety), Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Bolormaa Sunduimijid
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia
| | - Ruidong Xiang
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia.,Faculty of Veterinary & Agricultural Science, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Ralph Behrendt
- Agriculture Victoria, Hamilton Centre, Hamilton, VIC, 3300, Australia
| | - Matthew I Knight
- Agriculture Victoria, Hamilton Centre, Hamilton, VIC, 3300, Australia
| | - Brett A Mason
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia
| | - Coralie M Reich
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia
| | - Claire Prowse-Wilkins
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia
| | - Christy J Vander Jagt
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia
| | - Amanda J Chamberlain
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia
| | - Iona M MacLeod
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia
| | - Fadi Li
- State Key Laboratory of Grassland Agro-ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Grassland Agriculture Engineering Center, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, 730020, People's Republic of China
| | - Xiangpeng Yue
- State Key Laboratory of Grassland Agro-ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Grassland Agriculture Engineering Center, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, 730020, People's Republic of China.
| | - Hans D Daetwyler
- Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC, 3083, Australia. .,School of Applied Systems Biology, La Trobe University, Bundoora, VIC, 3083, Australia.
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37
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Blencowe M, Ahn IS, Saleem Z, Luk H, Cely I, Mäkinen VP, Zhao Y, Yang X. Gene networks and pathways for plasma lipid traits via multitissue multiomics systems analysis. J Lipid Res 2021; 62:100019. [PMID: 33561811 PMCID: PMC7873371 DOI: 10.1194/jlr.ra120000713] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 12/04/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
Genome-wide association studies (GWASs) have implicated ∼380 genetic loci for plasma lipid regulation. However, these loci only explain 17-27% of the trait variance, and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely, total cholesterol, high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides, from GWASs were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in "interferon signaling," "autoimmune/immune activation," "visual transduction," and "protein catabolism" were significantly associated with all lipid traits. In addition, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL; glutathione metabolism for HDL; valine, leucine, and isoleucine biosynthesis for total cholesterol; and insulin signaling and complement pathways for triglyceride. Finally, by using gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g., APOH, APOA4, and ABCA1) and novel (e.g., F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (coagulation factor II, thrombin) in 3T3-L1 and C3H10T1/2 adipocytes altered gene expression of Abcb11, Apoa5, Apof, Fabp1, Lipc, and Cd36; reduced intracellular adipocyte lipid content; and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.
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Affiliation(s)
- Montgomery Blencowe
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA
| | - In Sook Ahn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Zara Saleem
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Helen Luk
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Ingrid Cely
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Ville-Petteri Mäkinen
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA; South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Yuqi Zhao
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA; Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA.
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38
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Kottyan LC, Trimarchi MP, Lu X, Caldwell JM, Maddox A, Parameswaran S, Lape M, D'Mello RJ, Bonfield M, Ballaban A, Mukkada V, Putnam PE, Abonia P, Ben-Baruch Morgenstern N, Eapen AA, Wen T, Weirauch MT, Rothenberg ME. Replication and meta-analyses nominate numerous eosinophilic esophagitis risk genes. J Allergy Clin Immunol 2021; 147:255-266. [PMID: 33446330 PMCID: PMC8082436 DOI: 10.1016/j.jaci.2020.10.018] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Eosinophilic esophagitis (EoE) is an emerging, chronic, rare allergic disease associated with marked eosinophil accumulation in the esophagus. Previous genome-wide association studies have provided strong evidence for 3 genome-wide susceptibility loci. OBJECTIVE We sought to replicate known and suggestive EoE genetic risk loci and conduct a meta-analysis of previously reported data sets. METHODS An EoE-Custom single-nucleotide polymophism (SNP) Chip containing 956 candidate EoE risk single-nucleotide polymorphisms was used to genotype 627 cases and 365 controls. Statistical power was enhanced by adding 1959 external controls and performing meta-analyses with 2 independent EoE genome-wide association studies. RESULTS Meta-analysis identified replicated association and genome-wide significance at 6 loci: 2p23 (2 independent genetic effects) and 5q22, 10p14, 11q13, and 16p13. Seven additional loci were identified at suggestive significance (P < 10-6): 1q31, 5q23, 6q15, 6q21, 8p21, 17q12, and 22q13. From these risk loci, 13 protein-coding EoE candidate risk genes were expressed in a genotype-dependent manner. EoE risk genes were expressed in disease-relevant cell types, including esophageal epithelia, fibroblasts, and immune cells, with some expressed as a function of disease activity. The genetic risk burden of EoE-associated genetic variants was markedly larger in cases relative to controls (P < 10-38); individuals with the highest decile of genetic burden had greater than 12-fold risk of EoE compared with those within the lowest decile. CONCLUSIONS This study extends the genetic underpinnings of EoE, highlighting 13 genes whose genotype-dependent expression expands our etiologic understanding of EoE and provides a framework for a polygenic risk score to be validated in future studies.
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Affiliation(s)
- Leah C Kottyan
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Michael P Trimarchi
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Xiaoming Lu
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Julie M Caldwell
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Avery Maddox
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Sreeja Parameswaran
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Michael Lape
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Graduate Program in Biomedical Informatics, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Rahul J D'Mello
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Immunology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Madeline Bonfield
- Immunology Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Adina Ballaban
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Vincent Mukkada
- Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Philip E Putnam
- Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Pablo Abonia
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | | | - Amy A Eapen
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ting Wen
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Matthew T Weirauch
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Marc E Rothenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio.
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Lamb JR, Jennings LL, Gudmundsdottir V, Gudnason V, Emilsson V. It's in Our Blood: A Glimpse of Personalized Medicine. Trends Mol Med 2021; 27:20-30. [PMID: 32988739 PMCID: PMC11082297 DOI: 10.1016/j.molmed.2020.09.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/05/2020] [Accepted: 09/02/2020] [Indexed: 01/24/2023]
Abstract
Recent advances in protein profiling technology has facilitated simultaneous measurement of thousands of proteins in large population studies, exposing the depth and complexity of the plasma and serum proteomes. This revealed that proteins in circulation were organized into regulatory modules under genetic control and closely associated with current and future common diseases. Unlike networks in solid tissues, serum protein networks comprise members synthesized across different tissues of the body. Genetic analysis reveals that this cross-tissue regulation of the serum proteome participates in systemic homeostasis and mirrors the global disease state of individuals. Here, we discuss how application of this information in routine clinical evaluations may transform the future practice of medicine.
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Affiliation(s)
| | - Lori L Jennings
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
| | - Valborg Gudmundsdottir
- Icelandic Heart Association, IS-201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
| | - Vilmundur Gudnason
- Icelandic Heart Association, IS-201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
| | - Valur Emilsson
- Icelandic Heart Association, IS-201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
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40
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Chen YC, Wu MY, Yu ZL, Chou WH, Lai YT, Kao CC, Faridah IN, Wu MS, Chang WC. Association of UBE3C Variants with Reduced Kidney Function in Patients with Diabetic Kidney Disease. J Pers Med 2020; 10:jpm10040210. [PMID: 33171965 PMCID: PMC7712123 DOI: 10.3390/jpm10040210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/01/2020] [Accepted: 11/04/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM) and the most common variant of end-stage renal disease (ESRD) globally. The economic burden of ESRD treatment with dialysis is substantial. The incidence and prevalence of ESRD in Taiwan remain the highest worldwide. Therefore, identifying genetic factors affecting kidney function would have valuable clinical implications. We performed microarray experiments and identified that ubiquitin protein ligase E3C (UBE3C) is differentially expressed in two DKD patient groups with extreme (low and high) urine protein-to-creatinine ratios. A follow-up genotyping study was performed in a larger group to investigate any specific variants of UBE3C associated with DKD. A total of 263 patients were included in the study, comprising 172 patients with DKD and 91 control subjects (patients with DM without chronic kidney disease (CKD)). Two UBE3C variants (rs3802129(AA) and rs7807(CC)) were determined to be associated with reduced kidney function. The haplotype analysis revealed that rs3802129/rs3815217 (block 1) with A/G haplotype and rs8101/rs7807 (block 2) with T/C haplotype were associated with higher risks of CKD phenotypes. These findings suggest a clinical role of UBE3C variants in DKD risk.
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Affiliation(s)
- Ying-Chun Chen
- Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; (Y.-C.C.); (M.-Y.W.)
- Department of Pharmacy, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
| | - Mei-Yi Wu
- Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; (Y.-C.C.); (M.-Y.W.)
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
| | - Zhi-Lei Yu
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.Y.); (W.-H.C.); (Y.-T.L.); (I.N.F.)
| | - Wan-Hsuan Chou
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.Y.); (W.-H.C.); (Y.-T.L.); (I.N.F.)
| | - Yi-Ting Lai
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.Y.); (W.-H.C.); (Y.-T.L.); (I.N.F.)
| | - Chih-Chin Kao
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
| | - Imaniar Noor Faridah
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.Y.); (W.-H.C.); (Y.-T.L.); (I.N.F.)
- Faculty of Pharmacy, University of Ahmad Dahlan, Yogyakarta 55164, Indonesia
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (M.-S.W.); (W.-C.C.)
| | - Wei-Chiao Chang
- Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; (Y.-C.C.); (M.-Y.W.)
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; (Z.-L.Y.); (W.-H.C.); (Y.-T.L.); (I.N.F.)
- Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
- Correspondence: (M.-S.W.); (W.-C.C.)
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Dong Z, Ma Y, Zhou H, Shi L, Ye G, Yang L, Liu P, Zhou L. Integrated genomics analysis highlights important SNPs and genes implicated in moderate-to-severe asthma based on GWAS and eQTL datasets. BMC Pulm Med 2020; 20:270. [PMID: 33066754 PMCID: PMC7568423 DOI: 10.1186/s12890-020-01303-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 09/27/2020] [Indexed: 02/06/2023] Open
Abstract
Background Severe asthma is a chronic disease contributing to disproportionate disease morbidity and mortality. From the year of 2007, many genome-wide association studies (GWAS) have documented a large number of asthma-associated genetic variants and related genes. Nevertheless, the molecular mechanism of these identified variants involved in asthma or severe asthma risk remains largely unknown. Methods In the current study, we systematically integrated 3 independent expression quantitative trait loci (eQTL) data (N = 1977) and a large-scale GWAS summary data of moderate-to-severe asthma (N = 30,810) by using the Sherlock Bayesian analysis to identify whether expression-related variants contribute risk to severe asthma. Furthermore, we performed various bioinformatics analyses, including pathway enrichment analysis, PPI network enrichment analysis, in silico permutation analysis, DEG analysis and co-expression analysis, to prioritize important genes associated with severe asthma. Results In the discovery stage, we identified 1129 significant genes associated with moderate-to-severe asthma by using the Sherlock Bayesian analysis. Two hundred twenty-eight genes were prominently replicated by using MAGMA gene-based analysis. These 228 replicated genes were enriched in 17 biological pathways including antigen processing and presentation (Corrected P = 4.30 × 10− 6), type I diabetes mellitus (Corrected P = 7.09 × 10− 5), and asthma (Corrected P = 1.72 × 10− 3). With the use of a series of bioinformatics analyses, we highlighted 11 important genes such as GNGT2, TLR6, and TTC19 as authentic risk genes associated with moderate-to-severe/severe asthma. With respect to GNGT2, there were 3 eSNPs of rs17637472 (PeQTL = 2.98 × 10− 8 and PGWAS = 3.40 × 10− 8), rs11265180 (PeQTL = 6.0 × 10− 6 and PGWAS = 1.99 × 10− 3), and rs1867087 (PeQTL = 1.0 × 10− 4 and PGWAS = 1.84 × 10− 5) identified. In addition, GNGT2 is significantly expressed in severe asthma compared with mild-moderate asthma (P = 0.045), and Gngt2 shows significantly distinct expression patterns between vehicle and various glucocorticoids (Anova P = 1.55 × 10− 6). Conclusions Our current study provides multiple lines of evidence to support that these 11 identified genes as important candidates implicated in the pathogenesis of severe asthma.
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Affiliation(s)
- Zhouzhou Dong
- Critical Care Unit, Ningbo Medical Center Lihuili Hospital, Taipei Medical University Ningbo Medical Center, Ningbo, Zhejiang, 315100, P.R. China
| | - Yunlong Ma
- Institute of Biomedical Big Data, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.,School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Hua Zhou
- Department of Respiratory Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Linhui Shi
- Critical Care Unit, Ningbo Medical Center Lihuili Hospital, Taipei Medical University Ningbo Medical Center, Ningbo, Zhejiang, 315100, P.R. China
| | - Gongjie Ye
- Critical Care Unit, Ningbo Medical Center Lihuili Hospital, Taipei Medical University Ningbo Medical Center, Ningbo, Zhejiang, 315100, P.R. China
| | - Lei Yang
- Critical Care Unit, Ningbo Medical Center Lihuili Hospital, Taipei Medical University Ningbo Medical Center, Ningbo, Zhejiang, 315100, P.R. China
| | - Panpan Liu
- Critical Care Unit, Ningbo Medical Center Lihuili Hospital, Taipei Medical University Ningbo Medical Center, Ningbo, Zhejiang, 315100, P.R. China
| | - Li Zhou
- Department of Immunology and Rheumatology, Ningbo Medical Center Lihuili Hospital, Taipei Medical University Ningbo Medical Center, Ningbo, Zhejiang, 315100, P.R. China.
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Aguilera J, Semmler J, Coronel C, Georgiopoulos G, Simpson J, Nicolaides KH, Charakida M. Paired maternal and fetal cardiac functional measurements in women with gestational diabetes mellitus at 35-36 weeks' gestation. Am J Obstet Gynecol 2020; 223:574.e1-574.e15. [PMID: 32335051 DOI: 10.1016/j.ajog.2020.04.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/13/2020] [Accepted: 04/20/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Gestational diabetes mellitus is associated with early-onset cardiovascular disease and increased incidence of adverse cardiovascular outcomes in mothers and their offspring. Few studies with a limited number of patients have reported subclinical cardiac changes in association with gestational diabetes mellitus; however, it remains unclear whether the mother and the fetus respond in a similar fashion to gestational diabetes mellitus; thus, by assessing the heart of one, we can estimate or predict changes in the other. OBJECTIVE This study aimed to compare maternal and fetal cardiovascular functions in the third trimester between women with gestational diabetes mellitus and women with uncomplicated pregnancy and to explore whether gestational diabetes mellitus affects to the same extent the maternal and fetal heart. STUDY DESIGN This was a cross-sectional study of maternal and fetal echocardiography for assessment of cardiovascular function in the third trimester in women with singleton pregnancies who received a diagnosis of gestational diabetes mellitus and the control group with uncomplicated pregnancies. RESULTS In this study, we included 161 women with gestational diabetes mellitus and 483 women with uncomplicated pregnancies. Compared with women in the control group, women with gestational diabetes mellitus were older (34.5, standard deviation, 5.3 years] vs 32.5, standard deviation, 4.8 years]; P<.001), had higher body mass index (31.3 kg/m2 [standard deviation, 5.8] vs 28.6 kg/m2 [standard deviation, 4.4]; P<.001), had lower weight gain during pregnancy (8.3 [interquartile range, 4.8-11 kg] vs 10.8 [interquartile range, 8.2-13.5 kg]; P<.001), and delivered babies with lower birthweight (P<.001). After multivariable analysis, accounting for differences in maternal characteristics and fetal weight, mothers with gestational diabetes mellitus had lower left ventricular diastolic and systolic (tissue Doppler systolic [s'] wave) functional indices (P<.01 for both) compared with those of mothers in the control group. The noted cardiac changes did not fulfill the adult criteria for clinical cardiac dysfunction. No differences in hemodynamic indices (cardiac output and peripheral vascular resistance) and left ventricular mass were noted between the groups. Fetuses of mothers with gestational diabetes mellitus had more globular-shaped hearts with increased right and left ventricular sphericity indices (P<.001 for both) and reduced global longitudinal right and left ventricular systolic functional indices (P<.001 for both). The effect of gestational diabetes mellitus on maternal and fetal hearts was different, and there was no clear association between the two. CONCLUSION In the third trimester, in pregnancies with gestational diabetes mellitus, there were subclinical cardiac changes in both the mother and the fetus, but there was no significant difference in any of the fetal cardiac parameters between women with and women without unfavorable cardiac profile. This suggests that the stimulus for cardiovascular responses in the mother and fetus may not be the same in pregnancies with gestational diabetes mellitus.
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Pleiotropic genomic variants at 17q21.31 associated with bone mineral density and body fat mass: a bivariate genome-wide association analysis. Eur J Hum Genet 2020; 29:553-563. [PMID: 32963334 DOI: 10.1038/s41431-020-00727-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 09/01/2020] [Accepted: 09/04/2020] [Indexed: 12/19/2022] Open
Abstract
Osteoporosis and obesity are two severe complex diseases threatening public health worldwide. Both diseases are under strong genetic determinants as well as genetically correlated. Aiming to identify pleiotropic genes underlying obesity and osteoporosis, we performed a bivariate genome-wide association (GWA) meta-analysis of hip bone mineral density (BMD) and total body fat mass (TBFM) in 12,981 participants from seven samples, and followed by in silico replication in the UK biobank (UKB) cohort sample (N = 217,822). Combining the results from discovery meta-analysis and replication sample, we identified one novel locus, 17q21.31 (lead SNP rs12150327, NC_000017.11:g.44956910G > A, discovery bivariate P = 4.83 × 10-9, replication P = 5.75 × 10-5) at the genome-wide significance level (ɑ = 5.0 × 10-8), which may have pleiotropic effects to both hip BMD and TBFM. Functional annotations highlighted several candidate genes, including KIF18B, C1QL1, and PRPF19 that may exert pleiotropic effects to the development of both body mass and bone mass. Our findings can improve our understanding of the etiology of osteoporosis and obesity, as well as shed light on potential new therapies.
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Ma X, Wang P, Xu G, Yu F, Ma Y. Integrative genomics analysis of various omics data and networks identify risk genes and variants vulnerable to childhood-onset asthma. BMC Med Genomics 2020; 13:123. [PMID: 32867763 PMCID: PMC7457797 DOI: 10.1186/s12920-020-00768-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 08/17/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Childhood-onset asthma is highly affected by genetic components. In recent years, many genome-wide association studies (GWAS) have reported a large group of genetic variants and susceptible genes associated with asthma-related phenotypes including childhood-onset asthma. However, the regulatory mechanisms of these genetic variants for childhood-onset asthma susceptibility remain largely unknown. METHODS In the current investigation, we conducted a two-stage designed Sherlock-based integrative genomics analysis to explore the cis- and/or trans-regulatory effects of genome-wide SNPs on gene expression as well as childhood-onset asthma risk through incorporating a large-scale GWAS data (N = 314,633) and two independent expression quantitative trait loci (eQTL) datasets (N = 1890). Furthermore, we applied various bioinformatics analyses, including MAGMA gene-based analysis, pathway enrichment analysis, drug/disease-based enrichment analysis, computer-based permutation analysis, PPI network analysis, gene co-expression analysis and differential gene expression analysis, to prioritize susceptible genes associated with childhood-onset asthma. RESULTS Based on comprehensive genomics analyses, we found 31 genes with multiple eSNPs to be convincing candidates for childhood-onset asthma risk; such as, PSMB9 (cis-rs4148882 and cis-rs2071534) and TAP2 (cis-rs9267798, cis-rs4148882, cis-rs241456, and trans-10,447,456). These 31 genes were functionally interacted with each other in our PPI network analysis. Our pathway enrichment analysis showed that numerous KEGG pathways including antigen processing and presentation, type I diabetes mellitus, and asthma were significantly enriched to involve in childhood-onset asthma risk. The co-expression patterns among 31 genes were remarkably altered according to asthma status, and 25 of 31 genes (25/31 = 80.65%) showed significantly or suggestively differential expression between asthma group and control group. CONCLUSIONS We provide strong evidence to highlight 31 candidate genes for childhood-onset asthma risk, and offer a new insight into the genetic pathogenesis of childhood-onset asthma.
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Affiliation(s)
- Xiuqing Ma
- Department of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing, 100853 China
| | - Peilan Wang
- Outpatient Department, Chinese PLA General Hospital, Beijing, 100853 China
| | - Guobing Xu
- Department of Cardiovascular Medicine, Zhongxiang People’s Hospital, Zhongxiang, 431900 Hubei Province China
| | - Fang Yu
- Department of Pediatrics, Chinese PLA General Hospital, Beijing, 100853 China
| | - Yunlong Ma
- Institute of Biomedical Big Data, School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027 P. R. China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, China
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Nho K, Nudelman K, Allen M, Hodges A, Kim S, Risacher SL, Apostolova LG, Lin K, Lunnon K, Wang X, Burgess JD, Ertekin-Taner N, Petersen RC, Wang L, Qi Z, He A, Neuhaus I, Patel V, Foroud T, Faber KM, Lovestone S, Simmons A, Weiner MW, Saykin AJ. Genome-wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology. Alzheimers Dement 2020; 16:1213-1223. [PMID: 32755048 DOI: 10.1002/alz.12092] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 01/23/2020] [Accepted: 02/21/2020] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD). METHODS We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis. RESULTS We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10-8 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [18 F]Florbetapir positron emission tomography and CSF Aβ1-42 . DISCUSSION RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
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Affiliation(s)
- Kwangsik Nho
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kelly Nudelman
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana.,Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.,National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University, Indiana
| | - Mariet Allen
- Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida
| | - Angela Hodges
- Psychology & Neuroscience, Institute of Psychiatry, King's college London, London, UK
| | - Sungeun Kim
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana.,Department of Electrical and Computer Engineering, State University of New York, Oswego, New York
| | - Shannon L Risacher
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana
| | - Liana G Apostolova
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kuang Lin
- Psychology & Neuroscience, Institute of Psychiatry, King's college London, London, UK
| | | | - Xue Wang
- Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, Florida
| | - Jeremy D Burgess
- Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida
| | - Nilüfer Ertekin-Taner
- Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida.,Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida
| | - Ronald C Petersen
- Department of Neurology, Mayo Clinic Minnesota, Rochester, Minnesota
| | - Lisu Wang
- Bristol-Meyers Squibb, Wallingford, Connecticut
| | - Zhenhao Qi
- Bristol-Meyers Squibb, Wallingford, Connecticut
| | - Aiqing He
- Bristol-Meyers Squibb, Wallingford, Connecticut
| | | | | | - Tatiana Foroud
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana.,Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.,National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University, Indiana
| | - Kelley M Faber
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.,National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University, Indiana
| | | | - Andrew Simmons
- Psychology & Neuroscience, Institute of Psychiatry, King's college London, London, UK
| | - Michael W Weiner
- Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, California.,Department of Veterans Affairs Medical Center, San Francisco, California
| | - Andrew J Saykin
- Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana.,Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
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Dabbou S, Ferrocino I, Gasco L, Schiavone A, Trocino A, Xiccato G, Barroeta AC, Maione S, Soglia D, Biasato I, Cocolin L, Gai F, Nucera DM. Antimicrobial Effects of Black Soldier Fly and Yellow Mealworm Fats and Their Impact on Gut Microbiota of Growing Rabbits. Animals (Basel) 2020; 10:ani10081292. [PMID: 32731566 PMCID: PMC7460256 DOI: 10.3390/ani10081292] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/24/2020] [Accepted: 07/24/2020] [Indexed: 12/14/2022] Open
Abstract
This study aimed to evaluate the in vitro antimicrobial activities of two types of insect fats extracted from black soldier fly larvae (HI, Hermetia illucens L.) and yellow mealworm larvae (TM, Tenebrio molitor L.) and their effects as dietary replacement of soybean oil (S) on cecal fermentation pattern, and fecal and cecal microbiota in rabbits. A total of 120 weaned rabbits were randomly allotted to three dietary treatments (40 rabbits/group) -a control diet (C diet) containing 1.5% of S and two experimental diets (HI diet (HID) and TM diet (TMD)), where S was totally substituted by HI or TM fats during the whole trial that lasted 41 days. Regarding the in vitro antimicrobial activities, HI and TM fats did not show any effects on Salmonella growth. Yersinia enterocolitica showed significantly lower growth when challenged with HI fats than the controls. The insect fat supplementation in rabbit diets increased the contents of the cecal volatile fatty acids when compared to the control group. A metataxonomic approach was adopted to investigate the shift in the microbial composition as a function of the dietary insect fat supplementation. The microbiota did not show a clear separation as a function of the inclusion, even if a specific microbial signature was observed. Indeed, HI and TM fat supplementation enriched the presence of Akkermansia that was found to be correlated with NH3-N concentration. An increase in Ruminococcus, which can improve the immune response of the host, was also observed. This study confirms the potential of HI and TM fats as antibacterial feed ingredients with a positive influence on the rabbit cecal microbiota, thus supporting the possibility of including HI and TM fats in rabbit diets.
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Affiliation(s)
- Sihem Dabbou
- Center Agriculture Food Environment (C3A), University of Trento, Via E. Mach 1, 38010 San Michele all’Adige, Italy;
- Research and Innovation Centre, Fondazione Edmund Mach, 38010 San Michele all’Adige, Italy
| | - Ilario Ferrocino
- Department of Agricultural, Forest and Food Sciences, University of Torino, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (I.F.); (I.B.); (L.C.); (D.M.N.)
| | - Laura Gasco
- Department of Agricultural, Forest and Food Sciences, University of Torino, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (I.F.); (I.B.); (L.C.); (D.M.N.)
- Correspondence:
| | - Achille Schiavone
- Department of Veterinary Science, University of Turin, Largo P. Braccini 2, 10095 Grugliasco, Italy; (A.S.); (S.M.); (D.S.)
| | - Angela Trocino
- Department of Comparative Biomedicine and Food Science, University of Padova, Viale dell’Università 16, Legnaro, 35020 Padova, Italy;
| | - Gerolamo Xiccato
- Department of Agronomy, Food, Natural Resources, Animal, and Environment, University of Padova, Viale dell’Università 16, 35020 Legnaro, Padova, Italy;
| | - Ana C. Barroeta
- Nutrition and Animal Welfare Service, Department of Animal and Food Science, Faculty of Veterinary Medicine, Autonomous University of Barcelona, Bellaterra, 08193 Barcelona, Spain;
| | - Sandra Maione
- Department of Veterinary Science, University of Turin, Largo P. Braccini 2, 10095 Grugliasco, Italy; (A.S.); (S.M.); (D.S.)
| | - Dominga Soglia
- Department of Veterinary Science, University of Turin, Largo P. Braccini 2, 10095 Grugliasco, Italy; (A.S.); (S.M.); (D.S.)
| | - Ilaria Biasato
- Department of Agricultural, Forest and Food Sciences, University of Torino, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (I.F.); (I.B.); (L.C.); (D.M.N.)
| | - Luca Cocolin
- Department of Agricultural, Forest and Food Sciences, University of Torino, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (I.F.); (I.B.); (L.C.); (D.M.N.)
| | - Francesco Gai
- Institute of Sciences of Food Production, National Research Council, Largo Paolo Braccini 2, 10095 Grugliasco, Italy;
| | - Daniele Michele Nucera
- Department of Agricultural, Forest and Food Sciences, University of Torino, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (I.F.); (I.B.); (L.C.); (D.M.N.)
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Wang Q, Yi S, Du Z, Huang X, Xu J, Cao Q, Su G, Kijlstra A, Yang P. The Rs12569232 SNP Association with Vogt-Koyanagi-Harada Disease and Behcet's Disease is Probably Mediated by Regulation of Linc00467 Expression. Ocul Immunol Inflamm 2020; 29:1464-1470. [PMID: 32400232 DOI: 10.1080/09273948.2020.1745244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Purpose: To investigate whether the rs12569232 SNP association with Vogt-Koyanagi-Harada disease and Behcet's disease is mediated by regulation of Linc00467 expression.Methods: The expression of linc00467 was detected by real-time PCR. Adenovirus carrying the linc00467 was transduced into CD4+T cells and the effect on cell viability was measured by the CCK-8 test. Human proteome microarray and starBase 2.0 were used to identify the binding proteins of linc00467 and RNA Immunoprecipitation (RIP) was used to confirm the identity of bound proteins.Results: The rs12569232 was associated with the expression of linc00467. The expression of linc00467 was up-regulated in PBMCs and CD4+T cells from VKH disease and BD patients. Over-expression of linc00467 increased cell viability of CD4+T cells. HUR was the common binding protein identified by the two methods and confirmed by RIP.Conclusions: The rs12569232 association with VKH disease and BD may be mediated via regulating the expression of linc00467.
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Affiliation(s)
- Qingfeng Wang
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Shenglan Yi
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Ziyu Du
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xinyue Huang
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Jing Xu
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Qingfeng Cao
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Guannan Su
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Aize Kijlstra
- University Eye Clinic Maastricht, Maastricht, The Netherlands
| | - Peizeng Yang
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
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Fan J, Hu J, Xue C, Zhang H, Susztak K, Reilly MP, Xiao R, Li M. ASEP: Gene-based detection of allele-specific expression across individuals in a population by RNA sequencing. PLoS Genet 2020; 16:e1008786. [PMID: 32392242 PMCID: PMC7241832 DOI: 10.1371/journal.pgen.1008786] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 05/21/2020] [Accepted: 04/21/2020] [Indexed: 12/16/2022] Open
Abstract
Allele-specific expression (ASE) analysis, which quantifies the relative expression of two alleles in a diploid individual, is a powerful tool for identifying cis-regulated gene expression variations that underlie phenotypic differences among individuals. Existing methods for gene-level ASE detection analyze one individual at a time, therefore failing to account for shared information across individuals. Failure to accommodate such shared information not only reduces power, but also makes it difficult to interpret results across individuals. However, when only RNA sequencing (RNA-seq) data are available, ASE detection across individuals is challenging because the data often include individuals that are either heterozygous or homozygous for the unobserved cis-regulatory SNP, leading to sample heterogeneity as only those heterozygous individuals are informative for ASE, whereas those homozygous individuals have balanced expression. To simultaneously model multi-individual information and account for such heterogeneity, we developed ASEP, a mixture model with subject-specific random effect to account for multi-SNP correlations within the same gene. ASEP only requires RNA-seq data, and is able to detect gene-level ASE under one condition and differential ASE between two conditions (e.g., pre- versus post-treatment). Extensive simulations demonstrated the convincing performance of ASEP under a wide range of scenarios. We applied ASEP to a human kidney RNA-seq dataset, identified ASE genes and validated our results with two published eQTL studies. We further applied ASEP to a human macrophage RNA-seq dataset, identified genes showing evidence of differential ASE between M0 and M1 macrophages, and confirmed our findings by results from cardiometabolic trait-relevant genome-wide association studies. To the best of our knowledge, ASEP is the first method for gene-level ASE detection at the population level that only requires the use of RNA-seq data. With the growing adoption of RNA-seq, we believe ASEP will be well-suited for various ASE studies for human diseases.
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Affiliation(s)
- Jiaxin Fan
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Jian Hu
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Chenyi Xue
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York City, New York, United States of America
| | - Hanrui Zhang
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York City, New York, United States of America
| | - Katalin Susztak
- Departments of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Muredach P. Reilly
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York City, New York, United States of America
- The Irving Institute for Clinical and Translational Research, Columbia University Irving Medical Center, New York City, New York, United States of America
| | - Rui Xiao
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Mingyao Li
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
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Integrative genomics analysis of eQTL and GWAS summary data identifies PPP1CB as a novel bone mineral density risk genes. Biosci Rep 2020; 40:222598. [PMID: 32266926 PMCID: PMC7178214 DOI: 10.1042/bsr20193185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 03/03/2020] [Accepted: 04/03/2020] [Indexed: 11/17/2022] Open
Abstract
In recent years, multiple genome-wide association studies (GWAS) have identified numerous susceptibility variants and risk genes that demonstrate significant associations with bone mineral density (BMD). However, exploring how these genetic variants contribute risk to BMD remains a major challenge. We systematically integrated two independent expression quantitative trait loci (eQTL) data (N = 1890) and GWAS summary statistical data of BMD (N = 142,487) using Sherlock integrative analysis to reveal whether expression-associated variants confer risk to BMD. By using Sherlock integrative analysis and MAGMA gene-based analysis, we found there existed 36 promising genes, for example, PPP1CB, XBP1, and FDFT1, whose expression alterations may contribute susceptibility to BMD. Through a protein-protein interaction (PPI) network analysis, we further prioritized the PPP1CB as a hub gene that has interactions with predicted genes and BMD-associated genes. Two eSNPs of rs9309664 (PeQTL = 1.42 × 10-17 and PGWAS = 1.40 × 10-11) and rs7475 (PeQTL = 2.10 × 10-6 and PGWAS = 1.70 × 10-7) in PPP1CB were identified to be significantly associated with BMD risk. Consistently, differential gene expression analysis found that the PPP1CB gene showed significantly higher expression in low BMD samples than that in high BMD samples based on two independent expression datasets (P = 0.0026 and P = 0.043, respectively). Together, we provide a convergent line of evidence to support that the PPP1CB gene involves in the etiology of osteoporosis.
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Zhang J, Xie S, Gonzales S, Liu J, Wang X. A fast and powerful eQTL weighted method to detect genes associated with complex trait using GWAS summary data. Genet Epidemiol 2020; 44:550-563. [PMID: 32350919 DOI: 10.1002/gepi.22297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
Although genomewide association studies (GWASs) have identified many genetic variants underlying complex traits, a large fraction of heritability still remains unexplained. Integrative analysis that incorporates additional information, such as expression quantitativetrait locus (eQTL) data into sequencing studies (denoted as transcriptomewide association study [TWAS]), can aid the discovery of trait-associated genetic variants. However, general TWAS methods only incorporate one eQTL-derived weight (e.g., cis-effect), and thus can suffer a substantial loss of power when the single estimated cis-effect is not predictive for the effect size of a genetic variant or when there are estimation errors in the estimated cis-effect, or if the data are not consistent with the model assumption. In this study, we propose an omnibus test (OT) which utilizes a Cauchy association test to integrate association evidence demonstrated by three different traditional tests (burden test, quadratic test, and adaptive test) using GWAS summary data with multiple eQTL-derived weights. The p value of the proposed test can be calculated analytically, and thus it is fast and efficient. We applied our proposed test to two schizophrenia (SCZ) GWAS summary data sets and two lipids trait (HDL) GWAS summary data sets. Compared with the three traditional tests, our proposed OT can identify more trait-associated genes.
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Affiliation(s)
- Jianjun Zhang
- Department of Mathematics, University of North Texas, Denton, Texas
| | - Sicong Xie
- Beijing National Day School, Beijing, China
| | - Samantha Gonzales
- Department of Computer Science and Engineering, University of North Texas, Denton, Texas
| | - Jianguo Liu
- Department of Mathematics, University of North Texas, Denton, Texas
| | - Xuexia Wang
- Department of Mathematics, University of North Texas, Denton, Texas
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