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Ballem R, Andrés-Camazón P, Jensen KM, Bajracharya P, Díaz-Caneja CM, Bustillo JR, Turner JA, Fu Z, Chen J, Calhoun VD, Iraji A. Mapping the Psychosis Spectrum - Imaging Neurosubtypes from Multi-Scale Functional Network Connectivity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.11.637551. [PMID: 40196606 PMCID: PMC11974735 DOI: 10.1101/2025.02.11.637551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
This study aims to identify Psychosis Imaging Neurosubtypes (PINs)-homogeneous subgroups of individuals with psychosis characterized by distinct neurobiology derived from imaging features. Specifically, we utilized resting-state fMRI data from 2103 B-SNIP 1&2 participants (1127 with psychosis, 350 relatives, 626 controls) to compute subject-specific multiscale functional network connectivity (msFNC). We then derived a low-dimensional neurobiological subspace, termed Latent Network Connectivity (LNC), which captured system-wide interconnected multiscale information across three components (cognitive-related, typical, psychosis-related). Projections of psychosis participants' msFNC onto this subspace revealed three PINs through unsupervised learning, each with distinct cognitive, clinical, and connectivity profiles, spanning all DSM diagnoses (Schizophrenia, Bipolar, Schizoaffective). PIN-1, the most cognitively impaired, showed Cerebellar-Subcortical and Visual-Sensorimotor hypoconnectivity, alongside Visual-Subcortical hyperconnectivity. Most cognitively preserved PIN-2 showed Visual-Subcortical, Subcortical-Sensorimotor, and Subcortical-Higher Cognition hypoconnectivity. PIN-3 exhibited intermediate cognitive function, showing Cerebellar-Subcortical hypoconnectivity alongside Cerebellar-Sensorimotor and Subcortical-Sensorimotor hyperconnectivity. Notably, 55% of relatives aligned with the same neurosubtype as their affected family members-a significantly higher rate than random chance (p-valueRelatives-to-PIN-1 < 0.001, p-valueRelatives-to-PIN-2 < 0.05, p-valueRelatives-to-PIN-3 < 0.001) compared to a non-significant 37% DSM-based classification, supporting a biological basis of these neurosubtypes. Cognitive performance reliably aligns with distinct brain connectivity patterns, which are also evident in relatives, supporting their construct validity. Our PINs differed from original B-SNIP Biotypes, which were determined from electrophysiological, cognitive, and oculomotor data. These findings underscore the limitations of DSM-based classifications in capturing the biological complexity of psychotic disorders and highlight the potential of imaging-based neurosubtypes to enhance our understanding of the psychosis spectrum.
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Affiliation(s)
- Ram Ballem
- Georgia State University, Atlanta, USA
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
| | - Pablo Andrés-Camazón
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERSAM, ISCIII, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Kyle M. Jensen
- Georgia State University, Atlanta, USA
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
| | - Prerana Bajracharya
- Georgia State University, Atlanta, USA
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
| | - Covadonga M. Díaz-Caneja
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
| | - Juan R Bustillo
- Department of Psychiatry and Behavioral Sciences, University of New Mexico, Albuquerque, New Mexico
| | - Jessica A. Turner
- Department of Psychiatry and Behavioral Health, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Zening Fu
- Georgia State University, Atlanta, USA
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
| | - Jiayu Chen
- Georgia State University, Atlanta, USA
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
| | - Vince D. Calhoun
- Georgia State University, Atlanta, USA
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
| | - Armin Iraji
- Georgia State University, Atlanta, USA
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (Georgia State University, Georgia Institute of Technology, Emory University), Atlanta, USA
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Liu JJ, Borsari B, Li Y, Liu SX, Gao Y, Xin X, Lou S, Jensen M, Garrido-Martín D, Verplaetse TL, Ash G, Zhang J, Girgenti MJ, Roberts W, Gerstein M. Digital phenotyping from wearables using AI characterizes psychiatric disorders and identifies genetic associations. Cell 2025; 188:515-529.e15. [PMID: 39706190 DOI: 10.1016/j.cell.2024.11.012] [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: 10/26/2023] [Revised: 05/06/2024] [Accepted: 11/12/2024] [Indexed: 12/23/2024]
Abstract
Psychiatric disorders are influenced by genetic and environmental factors. However, their study is hindered by limitations on precisely characterizing human behavior. New technologies such as wearable sensors show promise in surmounting these limitations in that they measure heterogeneous behavior in a quantitative and unbiased fashion. Here, we analyze wearable and genetic data from the Adolescent Brain Cognitive Development (ABCD) study. Leveraging >250 wearable-derived features as digital phenotypes, we show that an interpretable AI framework can objectively classify adolescents with psychiatric disorders more accurately than previously possible. To relate digital phenotypes to the underlying genetics, we show how they can be employed in univariate and multivariate genome-wide association studies (GWASs). Doing so, we identify 16 significant genetic loci and 37 psychiatric-associated genes, including ELFN1 and ADORA3, demonstrating that continuous, wearable-derived features give greater detection power than traditional case-control GWASs. Overall, we show how wearable technology can help uncover new linkages between behavior and genetics.
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Affiliation(s)
- Jason J Liu
- Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT 06511, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
| | - Beatrice Borsari
- Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT 06511, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
| | - Yunyang Li
- Department of Computer Science, Yale University, New Haven, CT 06511, USA
| | - Susanna X Liu
- Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT 06511, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
| | - Yuan Gao
- Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT 06511, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
| | - Xin Xin
- Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT 06511, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
| | - Shaoke Lou
- Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT 06511, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
| | - Matthew Jensen
- Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT 06511, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
| | - Diego Garrido-Martín
- Department of Genetics, Microbiology and Statistics, Universitat de Barcelona (UB), Barcelona 08028, Spain
| | - Terril L Verplaetse
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Garrett Ash
- Section of General Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA; Center for Pain, Research, Informatics, Medical Comorbidities and Education Center (PRIME), VA Connecticut Healthcare System, West Haven, CT 06516, USA; Department of Biomedical Informatics and Data Science, Yale University, New Haven, CT 06511, USA
| | - Jing Zhang
- Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA
| | - Matthew J Girgenti
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Walter Roberts
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Biomedical Informatics and Data Science, Yale University, New Haven, CT 06511, USA.
| | - Mark Gerstein
- Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT 06511, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Department of Computer Science, Yale University, New Haven, CT 06511, USA; Department of Biomedical Informatics and Data Science, Yale University, New Haven, CT 06511, USA; Department of Statistics and Data Science, Yale University, New Haven, CT 06511, USA.
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Li X, Shen A, Fan L, Zhao Y, Xia J. PsyRiskMR: A Comprehensive Resource for Identifying Psychiatric Disorder Risk Factors Through Mendelian Randomization. Biol Psychiatry 2024:S0006-3223(24)01787-6. [PMID: 39643104 DOI: 10.1016/j.biopsych.2024.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 11/02/2024] [Accepted: 11/24/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND Psychiatric disorders pose an enormous economic and emotional burden on individuals, their families, and society. Given that the current analysis of the pathogenesis of psychiatric disorders remains challenging and time consuming, elucidating modifiable risk factors is crucial for the diagnosis and management of psychiatric disorders. However, inferring causal risk factors for these disorders from disparate data sources is challenging due to constraints in data collection and analytical capabilities. METHODS By leveraging the largest available genome-wide association study summary statistics for 10 psychiatric disorders and compiling an extensive set of risk factor datasets, including 71 psychiatric disorder-specific phenotypes, 3935 brain imaging traits, and over 30 brain tissue/cell-specific quantitative trait loci datasets (covering 6 types of quantitative trait loci), we performed comprehensive Mendelian randomization analyses to explore the potential causal links between various exposures and psychiatric outcomes using genetic variants as instrumental variables. RESULTS After Bonferroni correction for multiple testing, we identified multiple potential risk factors for psychiatric disorders (including phenotypic-level and molecular-level traits) and provided robust Mendelian randomization evidence that supports these associations utilizing rigorous sensitivity analyses and colocalization analyses. Furthermore, we have established the PsyRiskMR database (http://bioinfo.ahu.edu.cn/PsyRiskMR/), which serves as an interactive platform for showcasing and querying risk factors for psychiatric disorders. CONCLUSIONS Our study offers a user-friendly PsyRiskMR database for the research community to browse, search, and download all Mendelian randomization results, potentially revealing new insights into the biological etiology of psychiatric disorders.
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Affiliation(s)
- Xiaoyan Li
- Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China
| | - Aotian Shen
- Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China
| | - Lingli Fan
- Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China
| | - Yiran Zhao
- Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China
| | - Junfeng Xia
- Information Materials and Intelligent Sensing Laboratory of Anhui Province, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China.
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Tu EN, Duffy A. Editorial: Combining Genetic and Clinical Predictors of Bipolar Disorder: Towards Improving Diagnostic Precision in Youth. J Am Acad Child Adolesc Psychiatry 2024; 63:1081-1083. [PMID: 38762069 DOI: 10.1016/j.jaac.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 05/09/2024] [Indexed: 05/20/2024]
Abstract
Bipolar disorder (BD) is a complex, heterogeneous illness, with 60% to 85% of its variance attributed to genetic factors.1 Adolescence marks the first peak period of risk for the onset of BD, with the initial (hypo)manic episode often preceded by childhood psychopathology, including anxiety and sleep disorders, as well as internalizing symptoms.2 Given the non-specific nature of childhood antecedents, combined with the prominence of depressive episodes in the early illness course, accurate diagnosis is often delayed by 8 to 10 years from onset.3 Yet, the early course of BD in youth is already associated with significant morbidity and mortality. Therefore, more accurate and timely diagnosis is a priority. One way forward could be to combine biomarkers with clinical variables to help validate diagnoses, improve individual risk prediction and treatment, and advance discovery research into pathogenesis.
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Affiliation(s)
- En-Nien Tu
- University of Oxford, Oxford, United Kingdom, Chang Gung Memorial Hospital, Keelung, Taiwan, and Chang Gung University, Taoyuan City, Taiwan.
| | - Anne Duffy
- Queen's University, Kingston, Ontario, Canada, and University of Oxford, Oxford, United Kingdom
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Whittle S, Zhang L, Rakesh D. Environmental and neurodevelopmental contributors to youth mental illness. Neuropsychopharmacology 2024; 50:201-210. [PMID: 39030435 PMCID: PMC11526094 DOI: 10.1038/s41386-024-01926-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/03/2024] [Accepted: 07/09/2024] [Indexed: 07/21/2024]
Abstract
While a myriad of factors likely contribute to the development of mental illness in young people, the social environment (including early adverse experiences) in concert with neurodevelopmental alterations is undeniably important. A number of influential theories make predictions about how and why neurodevelopmental alterations may mediate or moderate the effects of the social environment on the emergence of mental illness. Here, we discuss current evidence supporting each of these theories. Although this area of research is rapidly growing, the body of evidence is still relatively limited. However, there exist some consistent findings, including increased striatal reactivity during positive affective processing and larger hippocampal volumes being associated with increased vulnerability or susceptibility to the effects of social environments on internalizing symptoms. Limited longitudinal work has investigated neurodevelopmental mechanisms linking the social environment with mental health. Drawing from human research and insights from animal studies, we propose an integrated mediation-moderation model and outline future research directions to advance the field.
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Affiliation(s)
- Sarah Whittle
- Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
- Orygen, Parkville, VIC, Australia.
| | - Lu Zhang
- Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia
- Orygen, Parkville, VIC, Australia
| | - Divyangana Rakesh
- Neuroimaging Department, Institute of Psychology, Psychiatry & Neuroscience, King's College London, London, UK
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Di Mento B, John JR, Diaz AM, Lin PI, Masi A, Grove R, Eapen V. Sex Differences in the Broad Autism Phenotype: Insights from the Australian Biobank. J Autism Dev Disord 2024:10.1007/s10803-024-06466-4. [PMID: 39023802 DOI: 10.1007/s10803-024-06466-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2024] [Indexed: 07/20/2024]
Abstract
Examining sub-threshold autistic traits in non-autistic first-degree relatives of individuals on the autism spectrum, known as the Broad Autism Phenotype (BAP), could provide new insights into the associations and familial aggregation of autistic traits. This study was a retrospective cross-sectional study of parents (n = 1008), probands with autism (n = 613), and unaffected siblings (n = 221) of probands with autism. BAP traits were examined by the BAP Questionnaire and Communication Checklist-Adult in parents, Autism Developmental Observation Scale-Second edition in probands, and Social Responsiveness Scale in siblings. Multivariable linear regression analyses were used to investigate the associations of parental BAP traits on autistic traits in probands and unaffected sibling BAP traits. Fathers showed significantly increased aloofness, pragmatic language difficulties, and social engagement problems compared to mothers. Female siblings showed increased difficulties with social cognition compared to male siblings. Adjusted models of the regression analyses showed that all BAP traits in fathers were significantly associated with BAP trait expression in probands with autism. Additionally, all of mother's BAP traits were significantly associated with unaffected siblings' BAP trait expression while only fathers' aloofness and rigidity traits were inversely associated with siblings' BAP trait expression. Finally, there were significant inverse interactions noted between parent's BAP traits and their children's BAP trait expression. This study demonstrated differences in how males and females express BAP traits and also identified differences in parent-child associations by sex, with fathers having a greater effect on their proband children's expression of BAP traits than mothers.
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Affiliation(s)
- Blaise Di Mento
- Discipline of Psychiatry and Mental health, Faculty of Medicine, UNSW Sydney, Randwick, NSW, Australia
| | - James Rufus John
- Discipline of Psychiatry and Mental health, Faculty of Medicine, UNSW Sydney, Randwick, NSW, Australia
| | - Antonio Mendoza Diaz
- Discipline of Psychiatry and Mental health, Faculty of Medicine, UNSW Sydney, Randwick, NSW, Australia
- Tasmanian Centre for Mental Health Service Innovation, Hobart, TAS, Australia
| | - Ping-I Lin
- Discipline of Psychiatry and Mental health, Faculty of Medicine, UNSW Sydney, Randwick, NSW, Australia
| | - Anne Masi
- Discipline of Psychiatry and Mental health, Faculty of Medicine, UNSW Sydney, Randwick, NSW, Australia
- Autism CRC, Long Pocket, Brisbane, QLD, Australia
| | - Rachel Grove
- School of Public Health, Faculty of Health, University of Technology Sydney, Ultimo, NSW, Australia
| | - Valsamma Eapen
- Discipline of Psychiatry and Mental health, Faculty of Medicine, UNSW Sydney, Randwick, NSW, Australia.
- Autism CRC, Long Pocket, Brisbane, QLD, Australia.
- Academic Unit of Infant Child and Adolescent Psychiatry Services (AUCS), South Western Sydney Local Health District, ICAMHS, L1 MHC, Liverpool Hospital, Elizabeth Street, Liverpool, 2170, NSW, Australia.
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Soleimani N, Calhoun VD. Neural Complexity Unveiled: Doubly Functionally Independent Primitives (dFIPs) in Psychiatric Risk Score Assessment. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2024; 2024:1-4. [PMID: 40039582 DOI: 10.1109/embc53108.2024.10781623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
Understanding and predicting intricate neural underpinnings of psychiatric disorders has become an area of intensive research in neuroimaging. Current assessment methods, such as genetic testing, face limitations in providing adaptable biomarkers. This study introduces an innovative perspective by focusing on doubly functionally independent primitives (dFIPs) to assess risk scores modeled by employing multiple linear regression. Departing from traditional polygenic risk scores, our novel approach assesses an individual's psychiatric risk by contrasting their functional network connectivity (FNC) with reference patterns from psychiatric disorder. Leveraging a large imaging dataset (N=5805) encompassing schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder (BPD) and major depressive disorder (MDD), alongside corresponding healthy controls, the risk score is computed and applied to a diverse dataset of Adolescent Brain and Cognitive Development (ABCD, N=8191). Our major findings unveiled the nuanced significance of reconstructed FNCs based on the most discriminative dFIP patterns in the 10% of the ABCD individuals with highest risk score for the specific disorder. Furthermore, the 10% ABCD individuals with highest risk score of ASD and MDD showed greater overlap than individuals with other disorders. Overall, these findings underscored the relative importance of each dFIP pattern, providing valuable insight into the differential contributions of these patterns to the accurate prediction of elevated risk score. Also, this pioneering approach provides a promising avenue for comprehensive risk assessment.
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Xie X, Zhou R, Fang Z, Zhang Y, Wang Q, Liu X. Seeing beyond words: Visualizing autism spectrum disorder biomarker insights. Heliyon 2024; 10:e30420. [PMID: 38694128 PMCID: PMC11061761 DOI: 10.1016/j.heliyon.2024.e30420] [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: 10/07/2023] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/04/2024] Open
Abstract
Objective This study employs bibliometric and visual analysis to elucidate global research trends in Autism Spectrum Disorder (ASD) biomarkers, identify critical research focal points, and discuss the potential integration of diverse biomarker modalities for precise ASD assessment. Methods A comprehensive bibliometric analysis was conducted using data from the Web of Science Core Collection database until December 31, 2022. Visualization tools, including R, VOSviewer, CiteSpace, and gCLUTO, were utilized to examine collaborative networks, co-citation patterns, and keyword associations among countries, institutions, authors, journals, documents, and keywords. Results ASD biomarker research emerged in 2004, accumulating a corpus of 4348 documents by December 31, 2022. The United States, with 1574 publications and an H-index of 213, emerged as the most prolific and influential country. The University of California, Davis, contributed significantly with 346 publications and an H-index of 69, making it the leading institution. Concerning journals, the Journal of Autism and Developmental Disorders, Autism Research, and PLOS ONE were the top three publishers of ASD biomarker-related articles among a total of 1140 academic journals. Co-citation and keyword analyses revealed research hotspots in genetics, imaging, oxidative stress, neuroinflammation, gut microbiota, and eye tracking. Emerging topics included "DNA methylation," "eye tracking," "metabolomics," and "resting-state fMRI." Conclusion The field of ASD biomarker research is dynamically evolving. Future endeavors should prioritize individual stratification, methodological standardization, the harmonious integration of biomarker modalities, and longitudinal studies to advance the precision of ASD diagnosis and treatment.
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Affiliation(s)
- Xinyue Xie
- The First Affiliated Hospital of Henan University of Chinese Medicine, Pediatrics Hospital, Zhengzhou, Henan, 450000, China
- Henan University of Chinese Medicine, School of Pediatrics, Zhengzhou, Henan, 450046, China
| | - Rongyi Zhou
- The First Affiliated Hospital of Henan University of Chinese Medicine, Pediatrics Hospital, Zhengzhou, Henan, 450000, China
- Henan University of Chinese Medicine, School of Pediatrics, Zhengzhou, Henan, 450046, China
| | - Zihan Fang
- Henan University of Chinese Medicine, School of Pediatrics, Zhengzhou, Henan, 450046, China
| | - Yongting Zhang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Pediatrics Hospital, Zhengzhou, Henan, 450000, China
- Henan University of Chinese Medicine, School of Pediatrics, Zhengzhou, Henan, 450046, China
| | - Qirong Wang
- Henan University of Chinese Medicine, School of Pediatrics, Zhengzhou, Henan, 450046, China
| | - Xiaomian Liu
- Henan University of Chinese Medicine, School of Medicine, Zhengzhou, Henan, 450046, China
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Yan W, Pearlson GD, Fu Z, Li X, Iraji A, Chen J, Sui J, Volkow ND, Calhoun VD. A Brainwide Risk Score for Psychiatric Disorder Evaluated in a Large Adolescent Population Reveals Increased Divergence Among Higher-Risk Groups Relative to Control Participants. Biol Psychiatry 2024; 95:699-708. [PMID: 37769983 PMCID: PMC10942727 DOI: 10.1016/j.biopsych.2023.09.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/14/2023] [Accepted: 09/16/2023] [Indexed: 10/03/2023]
Abstract
BACKGROUND Accurate psychiatric risk assessment requires biomarkers that are both stable and adaptable to development. Functional network connectivity (FNC), which steadily reconfigures over time, potentially contains abundant information to assess psychiatric risks. However, the absence of suitable analytical methodologies has constrained this area of investigation. METHODS We investigated the brainwide risk score (BRS), a novel FNC-based metric that contrasts the relative distances of an individual's FNC to that of psychiatric disorders versus healthy control references. To generate group-level disorder and healthy control references, we utilized a large brain imaging dataset containing 5231 total individuals diagnosed with schizophrenia, autism spectrum disorder, major depressive disorder, and bipolar disorder and their corresponding healthy control individuals. The BRS metric was employed to assess the psychiatric risk in 2 new datasets: Adolescent Brain Cognitive Development (ABCD) Study (n = 8191) and Human Connectome Project Early Psychosis (n = 170). RESULTS The BRS revealed a clear, reproducible gradient of FNC patterns from low to high risk for each psychiatric disorder in unaffected adolescents. We found that low-risk ABCD Study adolescent FNC patterns for each disorder were strongly present in over 25% of the ABCD Study participants and homogeneous, whereas high-risk patterns of each psychiatric disorder were strongly present in about 1% of ABCD Study participants and heterogeneous. The BRS also showed its effectiveness in predicting psychosis scores and distinguishing individuals with early psychosis from healthy control individuals. CONCLUSIONS The BRS could be a new image-based tool for assessing psychiatric vulnerability over time and in unaffected individuals, and it could also serve as a potential biomarker, facilitating early screening and monitoring interventions.
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Affiliation(s)
- Weizheng Yan
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, Georgia; National Institute on Alcohol Abuse and Alcoholism, Laboratory of Neuroimaging, National Institutes of Health, Bethesda, Maryland.
| | - Godfrey D Pearlson
- Department of Psychiatry and Neuroscience, Yale School of Medicine, New Haven, Connecticut
| | - Zening Fu
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, Georgia
| | - Xinhui Li
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, Georgia; School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, Georgia
| | - Armin Iraji
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, Georgia
| | - Jiayu Chen
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, Georgia
| | - Jing Sui
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, Georgia; State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China
| | - Nora D Volkow
- National Institute on Alcohol Abuse and Alcoholism, Laboratory of Neuroimaging, National Institutes of Health, Bethesda, Maryland
| | - Vince D Calhoun
- Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, Georgia.
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Chen Y, Shen Q, Lichtenstein P, Gradus JL, Arnberg FK, Larsson H, D’Onofrio BM, Fang F, Song H, Valdimarsdottir UA. Incidence Trajectories of Psychiatric Disorders After Assault, Injury, and Bereavement. JAMA Psychiatry 2024; 81:374-385. [PMID: 38231519 PMCID: PMC10794980 DOI: 10.1001/jamapsychiatry.2023.5156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 11/03/2023] [Indexed: 01/18/2024]
Abstract
Importance Traumatic events have been associated with elevated risks of psychiatric disorders, while the contributions of familial factors to these associations remain less clear. Objective To determine the contribution of familial factors to long-term incidence trajectories of psychiatric disorders following potentially traumatic events. Design, Setting, and Participants This cohort study evaluated 3 separate cohorts of individuals residing in Sweden who were free of previous diagnosed psychiatric disorders when first exposed to assault (n = 49 957), injury (n = 555 314), or bereavement (n = 321 263) from January 1987 to December 2013, together with their unexposed full siblings, and 10 age-, sex-, and birthplace-matched unexposed individuals (per exposed individual). Cohorts were created from the Swedish Total Population Register linked to health and population registers. Data were analyzed from March 2022 to April 2023. Exposures Potentially traumatic events, including various types of assault, injuries, and bereavement (death of a child or of a spouse or partner), were ascertained from the Swedish national registers. Main Outcomes and Measures Incident psychiatric disorders were ascertained from the Swedish Patient Register. Flexible parametric and Cox models were used to estimate associations of potentially traumatic events with incident psychiatric disorders after multivariable adjustment. Results The median (IQR) age at exposure to assault, injury, and bereavement was 22 (18-31), 19 (8-40), and 60 (51-68) years, respectively. During a median (IQR) follow-up of 4.9 (2.2-8.2), 9.1 (4.1-15.6), and 8.1 (3.4-14.8) years, the incidence rates of any psychiatric disorder were 38.1, 13.9, and 9.0 per 1000 person-years for the exposed groups of the 3 cohorts, respectively. Elevated risk of any psychiatric disorder was observed during the first year after exposure to any assault (hazard ratio [HR], 4.55; 95% CI, 4.34-4.77), injury (HR, 3.31; 95% CI,3.23-3.38), or bereavement (HR, 2.81; 95% CI, 2.72-2.91) and thereafter (assault HR, 2.50; 95% CI, 2.43-2.56; injury HR, 1.69; 95% CI, 1.68-1.70; bereavement HR, 1.42; 95% CI, 1.40-1.44). Comparable associations were obtained in sibling comparison (first year: assault HR, 3.70; 95% CI, 3.37-4.05; injury HR, 2.98; 95% CI, 2.85-3.12; bereavement HR, 2.72; 95% CI, 2.54-2.91; thereafter: assault HR, 1.93; 95% CI, 1.84-2.02; injury HR, 1.51; 95% CI, 1.48-1.53; bereavement HR, 1.35; 95% CI, 1.31-1.38). The risk elevation varied somewhat by type of traumatic events and psychiatric disorders, with the greatest HR noted for posttraumatic stress disorder after sexual assault (sibling comparison HR, 4.52; 95% CI, 3.56-5.73 during entire follow-up period). Conclusions and Relevance In this study, the long-term risk elevation of psychiatric disorders after potentially traumatic events was largely independent of familial factors. The risk elevation observed immediately after these events motivates early clinical surveillance and mental health services for these vulnerable populations.
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Affiliation(s)
- Yufeng Chen
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Qing Shen
- Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine, Shanghai, China
- Institute for Advanced Study, Tongji University, Shanghai, China
| | - Paul Lichtenstein
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
| | - Jaimie L. Gradus
- Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
- Department of Psychiatry, Boston University School of Public Health, Boston, Massachusetts
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Filip K. Arnberg
- National Centre for Disaster Psychiatry, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Henrik Larsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Brian M. D’Onofrio
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana
| | - Fang Fang
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Huan Song
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Unnur A. Valdimarsdottir
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
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11
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Sheng W, Fang S. Impact of Moral Elevation on College Students' Sense of Meaning of Life: The Mediating Roles of Gratitude and Perceived Social Support. Psychol Res Behav Manag 2024; 17:1103-1114. [PMID: 38505348 PMCID: PMC10949382 DOI: 10.2147/prbm.s441272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 02/22/2024] [Indexed: 03/21/2024] Open
Abstract
Purpose The current study examined the association between moral elevation and college students' sense of meaning of life, along with the potential mediating effects of gratitude and perceived social support on this relationship. Methods Using the convenience sampling method, the Moral Elevation Scale, the Sense of Meaning of Life Questionnaire, the Gratitude Questionnaire, and the Multidimensional Scale of Perceived Social Support were used to conduct questionnaire surveys on 1088 college students (Mage=19.59 years, SD=1.46). SPSS25.0 data statistics software was used to analyze the data, and the PROCESS macro for SPSS was used to conduct the mediation effect test. Results (1) Moral elevation was significantly and positively associated with college students' sense of meaning of life (β = 0.43,p < 0.001). (2) Both gratitude and perceived social support partially mediated the relation between moral elevation and sense of meaning of life. The indirect effect of moral elevation on sense of meaning of life via gratitude was 0.11 (95% CI = [0.0709, 0.1453]), and the mediating effect accounted for 52.71%. The indirect effect of moral elevation on sense of meaning of life via perceived social support was 0.06 (95% CI = [0.0385, 0.0863]), and the mediating effect accounted for 29.41%. (3) Gratitude and perceived social support sequentially mediated the association between moral elevation and sense of meaning of life, the indirect effect through gratitude and perceived social support was 0.04 (95% CI = [0.0237, 0.0512]) and accounted for 17.88%. Conclusion This study revealed the chain mediating roles of gratitude and perceived social support in the relation between moral elevation and sense of meaning of life for Chinese college students, which is of great theoretical and practical significance for the formation of a positive sense of meaning of life and the cultivation of moral elevation among college students.
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Affiliation(s)
- Wen Sheng
- School of Educational Science, Anhui Normal University, Wuhu, People’s Republic of China
| | - Shuanghu Fang
- School of Educational Science, Anhui Normal University, Wuhu, People’s Republic of China
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12
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Niu Y, Cai H, Zhang L. The Moderating Role of the DYX1C1 Gene in the Effect of Home Supervision on Chinese Children's Reading Achievements: Evidence from the Diathesis-Stress Model. Behav Sci (Basel) 2023; 13:891. [PMID: 37998638 PMCID: PMC10669724 DOI: 10.3390/bs13110891] [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: 09/14/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 11/25/2023] Open
Abstract
The current study aimed to explore whether susceptible children (with differences in DYX1C1 (dyslexia susceptibility 1 candidate gene 1) gene) are more likely to be influenced by either supportive or adverse home supervision in their reading achievements. Home supervision, reading achievements, and genotype data were collected from a total of 745 fourth and fifth grade children and their parents in Chongqing, China. The results showed that there was a significant interaction between the rs11629841 polymorphism of the DYX1C1 gene and home supervision on children's reading achievements. A further analysis based on the re-parameterized regression model showed that the interaction best fit a weak diathesis-stress model, which indicated that the home supervision had a stronger predictive effect on children's reading achievements among children with the susceptible genotype than children with a non-susceptible genotype in a more adverse environment rather than in a supportive environment. These results suggested that children carrying different genotypes may need targeted interventions and that their parents should emphasize home supervision to develop their children's reading skills.
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Affiliation(s)
- Yingnan Niu
- Collaborative Innovation Center of Assessment for Basic Education Quality, Beijing Normal University, No. 19, XinJieKouWai St., HaiDian District, Beijing 100875, China; (Y.N.); (H.C.)
| | - He Cai
- Collaborative Innovation Center of Assessment for Basic Education Quality, Beijing Normal University, No. 19, XinJieKouWai St., HaiDian District, Beijing 100875, China; (Y.N.); (H.C.)
| | - Li Zhang
- School of Sociology and Psychology, Central University of Finance and Economics, 39 South College Road, Haidian District, Beijing 100081, China
- Faculty of Psychology, Southwest University, Chongqing 400715, China
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13
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Vidovič E, Pelikan S, Atanasova M, Kouter K, Pileckyte I, Oblak A, Novak Šarotar B, Videtič Paska A, Bon J. DNA Methylation Patterns in Relation to Acute Severity and Duration of Anxiety and Depression. Curr Issues Mol Biol 2023; 45:7286-7303. [PMID: 37754245 PMCID: PMC10527760 DOI: 10.3390/cimb45090461] [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: 08/04/2023] [Revised: 08/31/2023] [Accepted: 09/05/2023] [Indexed: 09/28/2023] Open
Abstract
Depression and anxiety are common mental disorders that often occur together. Stress is an important risk factor for both disorders, affecting pathophysiological processes through epigenetic changes that mediate gene-environment interactions. In this study, we explored two proposed models about the dynamic nature of DNA methylation in anxiety and depression: a stable change, in which DNA methylation accumulates over time as a function of the duration of clinical symptoms of anxiety and depression, or a flexible change, in which DNA methylation correlates with the acute severity of clinical symptoms. Symptom severity was assessed using clinical questionnaires for anxiety and depression (BDI-II, IDS-C, and HAM-A), and the current episode and the total lifetime symptom duration was obtained from patients' medical records. Peripheral blood DNA methylation levels were determined for the BDNF, COMT, and SLC6A4 genes. We found a significant negative correlation between COMT_1 amplicon methylation and acute symptom scores, with BDI-II (R(22) = 0.190, p = 0.033), IDS-C (R(22) = 0.199, p = 0.029), and HAM-A (R(22) = 0.231, p = 0.018) all showing a similar degree of correlation. Our results suggest that DNA methylation follows flexible dynamics, with methylation levels closely associated with acute clinical presentation rather than with the duration of anxiety and depression. These results provide important insights into the dynamic nature of DNA methylation in anxiety and affective disorders and contribute to our understanding of the complex interplay between stress, epigenetics, and individual phenotype.
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Affiliation(s)
- Eva Vidovič
- University Psychiatric Clinic Ljubljana, 1260 Ljubljana, Slovenia (J.B.)
| | - Sebastian Pelikan
- University Psychiatric Clinic Ljubljana, 1260 Ljubljana, Slovenia (J.B.)
| | - Marija Atanasova
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Katarina Kouter
- Institute for Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Indre Pileckyte
- Center for Brain and Cognition, Pompeu Fabra University, 08018 Barcelona, Spain
| | - Aleš Oblak
- University Psychiatric Clinic Ljubljana, 1260 Ljubljana, Slovenia (J.B.)
| | - Brigita Novak Šarotar
- University Psychiatric Clinic Ljubljana, 1260 Ljubljana, Slovenia (J.B.)
- Department of Psychiatry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Alja Videtič Paska
- Institute for Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Jurij Bon
- University Psychiatric Clinic Ljubljana, 1260 Ljubljana, Slovenia (J.B.)
- Department of Psychiatry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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Büki G, Hadzsiev K, Bene J. Copy Number Variations in Neuropsychiatric Disorders. Int J Mol Sci 2023; 24:13671. [PMID: 37761973 PMCID: PMC10530736 DOI: 10.3390/ijms241813671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/23/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Neuropsychiatric disorders are complex conditions that represent a significant global health burden with complex and multifactorial etiologies. Technological advances in recent years have improved our understanding of the genetic architecture of the major neuropsychiatric disorders and the genetic loci involved. Previous studies mainly investigated genome-wide significant SNPs to elucidate the cross-disorder and disorder-specific genetic basis of neuropsychiatric disorders. Although copy number variations represent a major source of genetic variations, they are known risk factors in developing a variety of human disorders, including certain neuropsychiatric diseases. In this review, we demonstrate the current understanding of CNVs contributing to liability for schizophrenia, bipolar disorder, and major depressive disorder.
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Affiliation(s)
| | | | - Judit Bene
- Department of Medical Genetics, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary; (G.B.); (K.H.)
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15
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Castellini G, Merola GP, Baccaredda Boy O, Pecoraro V, Bozza B, Cassioli E, Rossi E, Bessi V, Sorbi S, Nacmias B, Ricca V. Emotional dysregulation, alexithymia and neuroticism: a systematic review on the genetic basis of a subset of psychological traits. Psychiatr Genet 2023; 33:79-101. [PMID: 36729042 PMCID: PMC10158611 DOI: 10.1097/ypg.0000000000000335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 11/24/2022] [Indexed: 02/03/2023]
Abstract
Neuroticism, alexithymia and emotion dysregulation are key traits and known risk factors for several psychiatric conditions. In this systematic review, the aim is to evaluate the genetic contribution to these psychological phenotypes. A systematic review of articles found in PubMed was conducted. Search terms included 'genetic', 'GWAS', 'neuroticism', 'alexithymia' and 'emotion dysregulation'. Risk of bias was assessed utilizing the STREGA checklist. Two hundred two papers were selected from existing literature based on the inclusion and exclusion criteria. Among these, 27 were genome-wide studies and 175 were genetic association studies. Single gene association studies focused on selected groups of genes, mostly involved in neurotransmission, with conflicting results. GWAS studies on neuroticism, on the other hand, found several relevant and replicated intergenic and intronic loci affecting the expression and regulation of crucial and well-known genes (such as DRD2 and CRHR1). Mutations in genes coding for trascriptional factors were also found to be associated with neuroticism (DCC, XKR6, TCF4, RBFOX1), as well as a noncoding regulatory RNA (LINC00461). On the other hand, little GWAS data are available on alexythima and emotional dysregulation.
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Affiliation(s)
| | | | | | | | | | | | | | - Valentina Bessi
- Neurology Unit, Department of Health Sciences, University of Florence, Florence, Italy
| | - Sandro Sorbi
- Neurology Unit, Department of Health Sciences, University of Florence, Florence, Italy
| | - Benedetta Nacmias
- Neurology Unit, Department of Health Sciences, University of Florence, Florence, Italy
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16
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Cuevas AG, Mann FD, Krueger RF. Discrimination Exposure and Polygenic Risk for Obesity in Adulthood: Testing Gene-Environment Correlations and Interactions. Lifestyle Genom 2023; 16:90-97. [PMID: 36750036 PMCID: PMC11078300 DOI: 10.1159/000529527] [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: 04/19/2022] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
INTRODUCTION Exposure to discrimination has emerged as a risk factor for obesity. It remains unclear, however, whether the genotype of the individual can modulate the sensitivity or response to discrimination exposure (gene × environment interaction) or increase the likelihood of experiencing discrimination (gene-environment correlation). METHODS This was an observational study of 4,102 white/European Americans in the Health and Retirement Study with self-reported, biological assessments, and genotyped data from 2006 to 2014. Discrimination was operationalized using the average of nine Everyday Discrimination Scale items. Polygenic risk scores (PRSs) for body mass index (BMI) and waist circumference (WC) were calculated using the weighted sum of risk alleles based on studies conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium. RESULTS We found that greater PRS-BMI was significantly associated with more reports of discrimination (β = 0.04 ± 0.02; p = 0.037). Further analysis showed that measured BMI partially mediated the association between PRS-BMI and discrimination. There was no evidence that the association between discrimination and BMI, or the association between discrimination and WC, differed by PRS-BMI or PRS-WC, respectively. CONCLUSION Our findings suggest that individuals with genetic liability for obesity may experience greater discrimination in their lifetime, consistent with a gene-environment correlation hypothesis. There was no evidence of a gene-environment interaction. More genome-wide association studies in diverse populations are needed to improve generalizability of study findings. In the meantime, prevention and clinical intervention efforts that seek to reduce exposure to all forms of discrimination may help reduce obesity at the population level.
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Affiliation(s)
- Adolfo G. Cuevas
- Department of Social and Behavioral Sciences Department, School of Global Public Health, New York University
| | - Frank D. Mann
- Department of Family, Population, and Preventative Medicine, Program in Public Health, Stony Brook University
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17
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Herrera-Imbroda J, Flores-López M, Ruiz-Sastre P, Gómez-Sánchez-Lafuente C, Bordallo-Aragón A, Rodríguez de Fonseca F, Mayoral-Cleríes F. The Inflammatory Signals Associated with Psychosis: Impact of Comorbid Drug Abuse. Biomedicines 2023; 11:biomedicines11020454. [PMID: 36830990 PMCID: PMC9953424 DOI: 10.3390/biomedicines11020454] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Psychosis and substance use disorders are two diagnostic categories whose association has been studied for decades. In addition, both psychosis spectrum disorders and drug abuse have recently been linked to multiple pro-inflammatory changes in the central nervous system. We have carried out a narrative review of the literature through a holistic approach. We used PubMed as our search engine. We included in the review all relevant studies looking at pro-inflammatory changes in psychotic disorders and substance use disorders. We found that there are multiple studies that relate various pro-inflammatory lipids and proteins with psychosis and substance use disorders, with an overlap between the two. The main findings involve inflammatory mediators such as cytokines, chemokines, endocannabinoids, eicosanoids, lysophospholipds and/or bacterial products. Many of these findings are present in different phases of psychosis and in substance use disorders such as cannabis, cocaine, methamphetamines, alcohol and nicotine. Psychosis and substance use disorders may have a common origin in an abnormal neurodevelopment caused, among other factors, by a neuroinflammatory process. A possible convergent pathway is that which interrelates the transcriptional factors NFκB and PPARγ. This may have future clinical implications.
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Affiliation(s)
- Jesús Herrera-Imbroda
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Facultad de Medicina, Universidad de Málaga, Andalucía Tech, Campus de Teatinos s/n, 29071 Málaga, Spain
- Departamento de Farmacología y Pediatría, Universidad de Málaga, Andalucía Tech, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - María Flores-López
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Facultad de Psicología, Universidad de Málaga, Andalucía Tech, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - Paloma Ruiz-Sastre
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Facultad de Medicina, Universidad de Málaga, Andalucía Tech, Campus de Teatinos s/n, 29071 Málaga, Spain
- Correspondence: (P.R.-S.); (C.G.-S.-L.)
| | - Carlos Gómez-Sánchez-Lafuente
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
- Facultad de Psicología, Universidad de Málaga, Andalucía Tech, Campus de Teatinos s/n, 29071 Málaga, Spain
- Correspondence: (P.R.-S.); (C.G.-S.-L.)
| | - Antonio Bordallo-Aragón
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Fernando Rodríguez de Fonseca
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Fermín Mayoral-Cleríes
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
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18
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Joyce DW, Kormilitzin A, Smith KA, Cipriani A. Explainable artificial intelligence for mental health through transparency and interpretability for understandability. NPJ Digit Med 2023; 6:6. [PMID: 36653524 PMCID: PMC9849399 DOI: 10.1038/s41746-023-00751-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 01/10/2023] [Indexed: 01/19/2023] Open
Abstract
The literature on artificial intelligence (AI) or machine learning (ML) in mental health and psychiatry lacks consensus on what "explainability" means. In the more general XAI (eXplainable AI) literature, there has been some convergence on explainability meaning model-agnostic techniques that augment a complex model (with internal mechanics intractable for human understanding) with a simpler model argued to deliver results that humans can comprehend. Given the differing usage and intended meaning of the term "explainability" in AI and ML, we propose instead to approximate model/algorithm explainability by understandability defined as a function of transparency and interpretability. These concepts are easier to articulate, to "ground" in our understanding of how algorithms and models operate and are used more consistently in the literature. We describe the TIFU (Transparency and Interpretability For Understandability) framework and examine how this applies to the landscape of AI/ML in mental health research. We argue that the need for understandablity is heightened in psychiatry because data describing the syndromes, outcomes, disorders and signs/symptoms possess probabilistic relationships to each other-as do the tentative aetiologies and multifactorial social- and psychological-determinants of disorders. If we develop and deploy AI/ML models, ensuring human understandability of the inputs, processes and outputs of these models is essential to develop trustworthy systems fit for deployment.
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Affiliation(s)
- Dan W Joyce
- University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX, UK.
- Institute of Population Health, Department of Primary Care and Mental Health, University of Liverpool, Liverpool, L69 3GF, UK.
| | - Andrey Kormilitzin
- University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX, UK
| | - Katharine A Smith
- University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX, UK
- Oxford Precision Psychiatry Lab, NIHR Oxford Health Biomedical Research Centre, Warneford Hospital, Oxford, OX3 7JX, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, OX3 7JX, UK
| | - Andrea Cipriani
- University of Oxford, Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX, UK
- Oxford Precision Psychiatry Lab, NIHR Oxford Health Biomedical Research Centre, Warneford Hospital, Oxford, OX3 7JX, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, OX3 7JX, UK
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Kurishev AO, Karpov DS, Nadolinskaia NI, Goncharenko AV, Golimbet VE. CRISPR/Cas-Based Approaches to Study Schizophrenia and Other Neurodevelopmental Disorders. Int J Mol Sci 2022; 24:241. [PMID: 36613684 PMCID: PMC9820593 DOI: 10.3390/ijms24010241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 12/24/2022] Open
Abstract
The study of diseases of the central nervous system (CNS) at the molecular level is challenging because of the complexity of neural circuits and the huge number of specialized cell types. Moreover, genomic association studies have revealed the complex genetic architecture of schizophrenia and other genetically determined mental disorders. Investigating such complex genetic architecture to decipher the molecular basis of CNS pathologies requires the use of high-throughput models such as cells and their derivatives. The time is coming for high-throughput genetic technologies based on CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)/Cas systems to manipulate multiple genomic targets. CRISPR/Cas systems provide the desired complexity, versatility, and flexibility to create novel genetic tools capable of both altering the DNA sequence and affecting its function at higher levels of genetic information flow. CRISPR/Cas tools make it possible to find and investigate the intricate relationship between the genotype and phenotype of neuronal cells. The purpose of this review is to discuss innovative CRISPR-based approaches for studying the molecular mechanisms of CNS pathologies using cellular models.
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Affiliation(s)
| | - Dmitry S. Karpov
- Mental Health Research Center, Kashirskoe sh. 34, 115522 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, 119991 Moscow, Russia
| | - Nonna I. Nadolinskaia
- Bach Institute of Biochemistry, Fundamentals of Biotechnology Federal Research Center, Russian Academy of Sciences, 119071 Moscow, Russia
| | - Anna V. Goncharenko
- Bach Institute of Biochemistry, Fundamentals of Biotechnology Federal Research Center, Russian Academy of Sciences, 119071 Moscow, Russia
| | - Vera E. Golimbet
- Mental Health Research Center, Kashirskoe sh. 34, 115522 Moscow, Russia
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Zhao X, Wu F, Shen G, Wang W, Yang S, Hu Y, Wu Y, Xu K, Zhao L, Shen X, Liu Y, Wang F, Chen L. Adiponectin. rs266729 Polymorphism and Nicotine Dependence Interaction: Genetic Investigations on the Anxiety Susceptibility. FRONT BIOSCI-LANDMRK 2022; 27:309. [PMID: 36472110 DOI: 10.31083/j.fbl2711309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND AIMS Nicotine dependence (ND)-induced anxiety might be modulated by genetic polymorphisms. The gene-by-environment interaction can be fitted into the diathesis-stress and differential susceptibility models. Nevertheless, knowledge of the interaction between adiponectin (ADPN) polymorphisms and ND on the incident mental disorder is currently scarce. This study aims to understand the role of ADPN rs266729 on anxiety in patients with ND while elucidating the psychology model and the various reactions across genotypes. METHODS We included 315 Chinese males with confirmed ND, measured using the Fagerstrom test for nicotine dependence (FTND). Anxiety was assessed using the Self-rating Anxiety Scale. Genomic DNA was extracted and genotyped from peripheral blood. Hierarchical regression models were used to test the interactions. RESULTS There was a significant interaction between ADPN rs266729 and ND (β = -0.19, p < 0.05). The CC homozygote was more likely to be affected by ND-induced anxiety (β = 0.14, t = 4.43, p < 0.01). Re-parameterized regression models revealed that the interaction between ADPN rs266729 and ND could fit the strong differential susceptibility model (R2 = 0.05, p < 0.001). CONCLUSIONS ADPN rs266729 was correlated with susceptibility to anxiety symptoms among male adults with ND and could fit the differential susceptibility model. The CC homozygote of rs266729 was a plasticity factor that increased anxiety symptoms in individuals with ND.
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Affiliation(s)
- Xudong Zhao
- Huzhou Third Municipal Hospital, The Affiliated Hospital of Wenzhou Medical University, 313000 Huzhou, Zhejiang, China
| | - Fenzan Wu
- Laboratory of Translational Medicine, Affiliated Cixi Hospital, Wenzhou Medical University, 315300 Ningbo, Zhejiang, China
| | - Guanghui Shen
- School of Mental Health, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China
| | - Wei Wang
- School of Mental Health, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China
| | - Shizhuo Yang
- School of Pharmacy, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China
| | - Yueling Hu
- School of Mental Health, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China
| | - Yuyu Wu
- School of Mental Health, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China
| | - Kewei Xu
- School of Mental Health, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China
| | - Lili Zhao
- Huzhou Third Municipal Hospital, The Affiliated Hospital of Wenzhou Medical University, 313000 Huzhou, Zhejiang, China
| | - Xinhua Shen
- Huzhou Third Municipal Hospital, The Affiliated Hospital of Wenzhou Medical University, 313000 Huzhou, Zhejiang, China
| | - Yanlong Liu
- School of Mental Health, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China
| | - Fan Wang
- Beijing Hui-Long-Guan Hospital, Peking University, 100096 Beijing, China
- Key Laboratory of Psychosomatic Medicine, Inner Mongolia Medical University, 010110 Hohhot, Inner Mongolia, China
| | - Li Chen
- The Affiliated Kangning Hospital, Wenzhou Medical University, 325035 Wenzhou, Zhejiang, China
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Brummelhuis IAM, Kop WJ, Videler AC. Psychological and physical wellbeing in adults who grew up with a mentally ill parent: A systematic mixed-studies review. Gen Hosp Psychiatry 2022; 79:162-176. [PMID: 36471514 DOI: 10.1016/j.genhosppsych.2022.09.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 09/21/2022] [Accepted: 09/26/2022] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Genetic vulnerability factors and adverse childhood experiences (ACE) are associated with an increased risk of psychopathology and other adverse health outcomes across the lifespan. However, less is known about how childhood experiences of parental mental illness affect psychological and physical wellbeing in adulthood. This review synthesizes research on the consequences of growing up as a child of a parent with mental illness (COPMI) for adult psychological and physical wellbeing. METHODS A systematic review was conducted following PRISMA guidelines using a mixed-method-studies approach to enable evaluation of the broad array of research designs (Prospero registration #CRD42020221983). RESULTS Qualitative studies (k = 10; N = 361) revealed that a COPMI background is associated with substantial psychological challenges in adulthood. Quantitative studies (k = 21; N = 865.402) suggested that COPMI are at increased risk of adult psychopathology, including anxiety and depressive disorders, suicidality, somatoform disorders, substance abuse, but also general medical morbidity and mortality. CONCLUSIONS Growing up with a mentally ill parent is associated with adverse psychological and physical outcomes in adulthood, but the evidence-base is limited. Longitudinal studies are needed that go beyond establishing genetic and environmental risk factors to further evaluate how a COPMI background influences wellbeing in adulthood and which targeted clinical interventions could be developed.
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Affiliation(s)
- Ingrid A M Brummelhuis
- Clinical Centre of Excellence for Body, Mind and Health, GGz Breburg, Tilburg, the Netherlands; Department Tranzo, Tilburg School of Social and Behavioral Sciences, Tilburg University, Tilburg, the Netherlands
| | - Willem J Kop
- Clinical Centre of Excellence for Body, Mind and Health, GGz Breburg, Tilburg, the Netherlands; Department of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands.
| | - Arjan C Videler
- Clinical Centre of Excellence for Body, Mind and Health, GGz Breburg, Tilburg, the Netherlands; Department Tranzo, Tilburg School of Social and Behavioral Sciences, Tilburg University, Tilburg, the Netherlands; Clinical Centre of Excellence for Personality Disorders and Autism in Older Adults, GGz Breburg, Tilburg, the Netherlands
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22
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Wei X, Cai F, Zhou S, Zhang J, Xu K, Shen G, Sun H, Yang F, Hong L, Zou Y, Chen YH, Liu Y, Chen L, Wang F, Wang W. The neuropeptide Y single-nucleotide polymorphism rs16147:T> C moderates the effect of alcohol dependence on depression in male Chinese Han population. Front Psychiatry 2022; 13:1012850. [PMID: 36245887 PMCID: PMC9558829 DOI: 10.3389/fpsyt.2022.1012850] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Previous studies suggest that alcohol dependence is associated with depression, however, the effect of alcohol dependence varies from individual to individual, which may be due to different genetic backgrounds. The interactions between alcohol dependence and different gene polymorphisms may finally shape the onset of depression. Neuropeptide Y (NPY), which can maintain homeostasis from high-stress stimulation, may protect individuals from the onset of depression. Here, we explored whether the NPY rs16147:T>C has an association with depression in individuals with alcohol dependence during the period of alcohol dependence withdrawal. METHODS A total of 455 males with alcohol dependence were recruited. The scale of Michigan Alcoholism Screening Test (MAST) and Self-Depression Scale (SDS) were respectively used to analyze the condition of alcohol dependence and depression. Genomic DNA was extracted from each blood sample and NPY polymorphisms were genotyped. The interaction between NPY rs16147:T>C and alcohol dependence on depression was first analyzed. Then, region of significance analysis was used to confirm which model provided the best fit for the interaction (diathesis-stress or differential susceptibility). Finally, by using internal replication analyses, the accuracy and robustness of the interaction results were improved. RESULTS Alcohol dependence was positively correlated with depression. CC homozygotes of NPY rs16147:T>C exhibited less depression when exposed to low alcohol dependence, but more depression when exposed to high alcohol dependence. Individuals with the T allele showed the opposite result. CONCLUSION NPY rs16147:T>C might be correlated with susceptibility for depression in males during alcohol dependence withdrawal. The findings support the differential susceptibility model.
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Affiliation(s)
- Xiaojie Wei
- Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, China
| | - Fangfang Cai
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Siyao Zhou
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Jinjing Zhang
- Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, China
| | - Kewei Xu
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Guanghui Shen
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Huankun Sun
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Fan Yang
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, China
| | - Liuzhi Hong
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Yang Zou
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Yu-Hsin Chen
- Department of Psychology, College of Liberal Arts, Wenzhou-Kean University, Wenzhou, China
| | - Yanlong Liu
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, China
| | - Li Chen
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, China
| | - Fan Wang
- Beijing Hui-Long-Guan Hospital, Peking University, Beijing, China
| | - Wei Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, China
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23
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Greenwood TA, Chow LJ, Gur RC, Kelsoe JR. Bipolar spectrum traits and the space between Madness and Genius: The Muse is in the Dose. J Psychiatr Res 2022; 153:149-158. [PMID: 35816974 DOI: 10.1016/j.jpsychires.2022.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 06/18/2022] [Accepted: 07/01/2022] [Indexed: 11/25/2022]
Abstract
Creativity has long been associated with the bipolar spectrum, particularly among unaffected first-degree relatives and those with milder expressions of bipolar traits, suggesting that some aspects of the bipolar spectrum may confer advantages for creativity. Here we took a multifaceted approach to better define the shared vulnerability between creativity and bipolar disorder. We recruited 135 individuals with bipolar disorder, 102 creative controls, and 103 non-creative controls for a total of 340 participants. All participants completed a comprehensive assessment battery that included several self-report temperament and personality questionnaires, a computerized test of cognitive function across multiple domains, and an evaluation of creative performance and achievement. Significant group differences were observed for the hypothesized shared vulnerability traits of hypomanic personality, cyclothymic temperament, impulsivity, and positive schizotypy. While both the creative and bipolar groups demonstrated superior creative ability, the creative group alone revealed enhanced cognitive performance. Accounting for intercorrelations between traits, a combination of openness, hypomanic personality, divergent thinking, and reasoning ability emerged as the strongest predictors of creativity, collectively explaining 34% of the variance in creative achievement and correctly classifying 85% of individuals with high achievement irrespective of diagnosis. These results confirm and extend earlier observations of a shared vulnerability between creativity and bipolar disorder and suggest that mild to moderate expressions of bipolar spectrum traits are associated with enhanced cognitive functioning and creative expression. Further investigation of these traits is needed to clarify the nature of this shared vulnerability and suggest individualized treatment strategies to improve clinical outcomes in bipolar disorder.
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Affiliation(s)
- Tiffany A Greenwood
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
| | - Lauren J Chow
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Ruben C Gur
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
| | - John R Kelsoe
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, UC San Diego, La Jolla, CA, USA
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24
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Gordillo D, da Cruz JR, Chkonia E, Lin WH, Favrod O, Brand A, Figueiredo P, Roinishvili M, Herzog MH. The EEG multiverse of schizophrenia. Cereb Cortex 2022; 33:3816-3826. [PMID: 36030389 PMCID: PMC10068296 DOI: 10.1093/cercor/bhac309] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/15/2022] [Accepted: 07/15/2022] [Indexed: 11/14/2022] Open
Abstract
Research on schizophrenia typically focuses on one paradigm for which clear-cut differences between patients and controls are established. Great efforts are made to understand the underlying genetical, neurophysiological, and cognitive mechanisms, which eventually may explain the clinical outcome. One tacit assumption of these "deep rooting" approaches is that paradigms tap into common and representative aspects of the disorder. Here, we analyzed the resting-state electroencephalogram (EEG) of 121 schizophrenia patients and 75 controls. Using multiple signal processing methods, we extracted 194 EEG features. Sixty-nine out of the 194 EEG features showed a significant difference between patients and controls, indicating that these features detect an important aspect of schizophrenia. Surprisingly, the correlations between these features were very low. We discuss several explanations to our results and propose that complementing "deep" with "shallow" rooting approaches might help in understanding the underlying mechanisms of the disorder.
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Affiliation(s)
- Dario Gordillo
- Corresponding author: Laboratory of Psychophysics, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
| | | | - Eka Chkonia
- Department of Psychiatry, Tbilisi State Medical University (TSMU), 0186 Tbilisi, Georgia
- Institute of Cognitive Neurosciences, Free University of Tbilisi, 0159 Tbilisi, Georgia
| | - Wei-Hsiang Lin
- Laboratory of Psychophysics, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Ophélie Favrod
- Laboratory of Psychophysics, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Andreas Brand
- Laboratory of Psychophysics, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Patrícia Figueiredo
- Institute for Systems and Robotics – Lisboa, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal
| | - Maya Roinishvili
- Institute of Cognitive Neurosciences, Free University of Tbilisi, 0159 Tbilisi, Georgia
- Laboratory of Vision Physiology, Ivane Beritashvili Centre of Experimental Biomedicine, 0160 Tbilisi, Georgia
| | - Michael H Herzog
- Laboratory of Psychophysics, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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25
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Soler CT, Kanders SH, Olofsdotter S, Vadlin S, Åslund C, Nilsson KW. Exploration of the Moderating Effects of Physical Activity and Early Life Stress on the Relation between Brain-Derived Neurotrophic Factor (BDNF) rs6265 Variants and Depressive Symptoms among Adolescents. Genes (Basel) 2022; 13:1236. [PMID: 35886019 PMCID: PMC9319123 DOI: 10.3390/genes13071236] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 02/04/2023] Open
Abstract
Depression affects one in five persons at 18 years of age. Allele A of the brain-derived neurotrophic factor (BDNF) rs6265 is considered to be a risk factor for depression. Previous studies of the interaction between BDNF rs6265, early adversity, and/or physical activity have shown mixed results. In this study, we explored the relation between BDNF rs6265 polymorphism and childhood stress, as well as the moderating effect of physical activity in relation to depressive symptoms using binary logistic regressions and process models 1, 2 and 3 applied to data obtained at three times (waves 1, 2 and 3) from the Survey of Adolescent Life in Västmanland cohort study (SALVe). Results revealed that both childhood stress and physical activity had a moderation effect; physical activity in wave 1 with an R2 change = 0.006, p = 0.013, and the Johnson−Neyman regions of significance (RoS) below 1.259, p = 0.05 for 11.97%; childhood stress in wave 2 with the R2 change = 0.008, p = 0 002, and RoS below 1.561 with 26.71% and >4.515 with 18.20%; and a three-way interaction in wave 1 in genotype AA carriers. These results suggest that allele A is susceptible to physical activity (positive environment) and childhood stress (negative environment).
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Affiliation(s)
- Catalina Torres Soler
- Centre for Clinical Research, Region Västmanland, Uppsala University, 72189 Västerås, Sweden; (C.T.S.); (S.O.); (S.V.); (C.Å.); (K.W.N.)
| | - Sofia H. Kanders
- Centre for Clinical Research, Region Västmanland, Uppsala University, 72189 Västerås, Sweden; (C.T.S.); (S.O.); (S.V.); (C.Å.); (K.W.N.)
| | - Susanne Olofsdotter
- Centre for Clinical Research, Region Västmanland, Uppsala University, 72189 Västerås, Sweden; (C.T.S.); (S.O.); (S.V.); (C.Å.); (K.W.N.)
- Department of Psychology, Uppsala University, 75142 Uppsala, Sweden
| | - Sofia Vadlin
- Centre for Clinical Research, Region Västmanland, Uppsala University, 72189 Västerås, Sweden; (C.T.S.); (S.O.); (S.V.); (C.Å.); (K.W.N.)
| | - Cecilia Åslund
- Centre for Clinical Research, Region Västmanland, Uppsala University, 72189 Västerås, Sweden; (C.T.S.); (S.O.); (S.V.); (C.Å.); (K.W.N.)
- Department of Public Health and Caring Sciences, Uppsala University, 75122 Uppsala, Sweden
| | - Kent W. Nilsson
- Centre for Clinical Research, Region Västmanland, Uppsala University, 72189 Västerås, Sweden; (C.T.S.); (S.O.); (S.V.); (C.Å.); (K.W.N.)
- The School of Health, Care and Social Welfare, Mälardalen University, 72123 Västerås, Sweden
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26
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Askeland RB, Hannigan LJ, Ask H, Ayorech Z, Tesli M, Corfield E, Magnus P, Njølstad PR, Andreassen OA, Smith GD, Reichborn-Kjennerud T, Havdahl A. Early manifestations of genetic risk for neurodevelopmental disorders. J Child Psychol Psychiatry 2022; 63:810-819. [PMID: 34605010 PMCID: PMC7616991 DOI: 10.1111/jcpp.13528] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/27/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (autism) and schizophrenia are highly heritable neurodevelopmental disorders, affecting the lives of many individuals. It is important to increase our understanding of how the polygenic risk for neurodevelopmental disorders manifests during childhood in boys and girls. METHODS Polygenic risk scores (PRS) for ADHD, autism and schizophrenia were calculated in a subsample of 15 205 children from the Norwegian Mother, Father and Child Cohort Study (MoBa). Mother-reported traits of repetitive behavior, social communication, language and motor difficulties, hyperactivity and inattention were measured in children at 6 and 18 months, 3, 5 and 8 years. Linear regression models in a multigroup framework were used to investigate associations between the three PRS and dimensional trait measures in MoBa, using sex as a grouping variable. RESULTS Before the age of 2, the ADHD PRS was robustly associated with hyperactivity and inattention, with increasing strength up to 8 years, and with language difficulties at age 5 and 8. The autism PRS was robustly associated with language difficulties at 18 months, motor difficulties at 36 months, and hyperactivity and inattention at 8 years. We did not identify robust associations for the schizophrenia PRS. In general, the PRS associations were similar in boys and girls. The association between ADHD PRS and hyperactivity at 18 months was, however, stronger in boys. CONCLUSIONS Polygenic risk for autism and ADHD in the general population manifests early in childhood and broadly across behavioral measures of neurodevelopmental traits.
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Affiliation(s)
- Ragna Bugge Askeland
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Laurie J. Hannigan
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Nic Waals Institute, Oslo, Norway
| | - Helga Ask
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
| | - Ziada Ayorech
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Nic Waals Institute, Oslo, Norway
| | - Martin Tesli
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Division of Mental Health and Addiction, NORMENT Centre, Oslo University Hospital, Oslo, Norway
| | - Elizabeth Corfield
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
| | - Per Magnus
- Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Pål Rasmus Njølstad
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Children and Adolescent Clinic, Haukeland University Hospital, Bergen, Norway
| | - Ole A. Andreassen
- Division of Mental Health and Addiction, NORMENT Centre, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, NORMENT Centre, University of Oslo, Oslo, Norway
| | - George Davey Smith
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Ted Reichborn-Kjennerud
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Alexandra Havdahl
- Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
- Nic Waals Institute, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
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Talaei A, Afzaljavan F, Rezaei S, Talaei A. Predictive value of the TNF-α-rs1800629 polymorphism in bipolar disorder: A case-control study and a meta-analysis. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101521] [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]
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28
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Mandal PK, Guha Roy R, Samkaria A, Maroon JC, Arora Y. In Vivo 13C Magnetic Resonance Spectroscopy for Assessing Brain Biochemistry in Health and Disease. Neurochem Res 2022; 47:1183-1201. [PMID: 35089504 DOI: 10.1007/s11064-022-03538-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 01/15/2022] [Accepted: 01/19/2022] [Indexed: 12/27/2022]
Abstract
Magnetic resonance spectroscopy (MRS) is a non-invasive technique that contributes to the elucidation of brain biochemistry. 13C MRS enables the detection of specific neurochemicals and their neuroenergetic correlation with neuronal function. The synergistic outcome of 13C MRS and the infusion of 13C-labeled substrates provide an understanding of neurometabolism and the role of glutamate/gamma-aminobutyric acid (GABA) neurotransmission in diseases, such as Alzheimer's disease, schizophrenia, and bipolar disorder. Moreover, 13C MRS provides a window into the altered flux rate of different pathways, including the tricarboxylic acid cycle (TCA) and the glutamate/glutamine/GABA cycle, in health and in various diseases. Notably, the metabolic flux rate of the TCA cycle often decreases in neurodegenerative diseases. Additionally, 13C MRS can be used to investigate several psychiatric and neurological disorders as it directly reflects the real-time production and alterations of key brain metabolites. This review aims to highlight the chronology, the technological advancements, and the applications of 13C MRS in various brain diseases.
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Affiliation(s)
- Pravat K Mandal
- Neuroimaging and Neurospectroscopy (NINS) Laboratory, National Brain Research Centre (NBRC), Gurgaon, India.
- Florey Institute of Neuroscience and Mental Health, Melbourne School of Medicine Campus, Melbourne, Australia.
| | - Rimil Guha Roy
- Neuroimaging and Neurospectroscopy (NINS) Laboratory, National Brain Research Centre (NBRC), Gurgaon, India
| | - Avantika Samkaria
- Neuroimaging and Neurospectroscopy (NINS) Laboratory, National Brain Research Centre (NBRC), Gurgaon, India
| | - Joseph C Maroon
- Department of Neurosurgery, University of Pittsburgh Medical School, Pittsburgh, PA, USA
| | - Yashika Arora
- Neuroimaging and Neurospectroscopy (NINS) Laboratory, National Brain Research Centre (NBRC), Gurgaon, India
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29
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Sun Z, Qin X, Fang J, Tang Y, Fan Y. Multi-Omics Analysis of the Expression and Prognosis for FKBP Gene Family in Renal Cancer. Front Oncol 2021; 11:697534. [PMID: 34476212 PMCID: PMC8406630 DOI: 10.3389/fonc.2021.697534] [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: 04/19/2021] [Accepted: 07/26/2021] [Indexed: 01/20/2023] Open
Abstract
Background The FK506-binding protein (FKBP) is a family of intracellular receptors that can bind specifically to the immunosuppressant FK506 and rapamycin. Although FKBPs play crucial roles in biological processes and carcinogenesis, their prognostic value and molecular mechanism in clear cell renal cell carcinoma (ccRCC) remain unclear. Methods Using pan-cancer data from The Cancer Genome Atlas (TCGA) and public databases, we analyzed the expression and correlation of FKBPs in 33 tumor types. Survival and Cox regression analyses were employed to explore the prognostic value of FKBPs. The relationship with tumor microenvironment and stemness indices was taken into account to evaluate the function of FKBPs. We constructed a risk score model to predict the prognosis of patients with ccRCC. The receiver operating characteristic (ROC) curve was performed to further test the prognostic ability of our model. Nomogram, joint effects analysis, and clinical relevance were performed to assist the clinician. Gene set enrichment analysis (GSEA) and cell line experiments were performed to investigate the function and molecular mechanisms of FKBPs in patients with ccRCC. Paired clinical specimens and multi-omics analysis were used to further validate and explore the factors affecting gene expression in ccRCC patients. Results The expression levels of FKBP10 and FKBP11 were higher in ccRCC tissues than in normal tissues. The alteration in expression may be because of the degree of DNA methylation. Increased expression levels of FKBP10 and FKBP11 were associated with worse overall survival (OS). More importantly, GSEA revealed that FKBP10 is mainly involved in cell metabolism and autophagy, whereas FKBP11 is mainly associated with immune-related biological processes and autophagy. Cell Counting Kit 8 (CCK-8) and Transwell assays revealed that knockdown of FKBP10 and FKBP11 inhibits proliferation, migration, and invasion of the ccRCC cell line. Conclusion FKBP10 and FKBP11 play important roles in ccRCC phenotypes and are potential prognostic markers as well as new therapeutic targets for patients with ccRCC.
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Affiliation(s)
- Zeqiang Sun
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Xin Qin
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Juanjuan Fang
- Department of Anesthesiology and Day Surgery, Dezhou People's Hospital, Dezhou, China
| | - Yueqing Tang
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
| | - Yidong Fan
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, China
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Chen JH, Zhao Y, Khan RAW, Li ZQ, Zhou J, Shen JW, Xiang SY, Li NN, Wen ZJ, Jian XM, Song ZJ, Stewart R, Wang Z, Pan D, He L, Xu YF, Shi YY. SNX29, a new susceptibility gene shared with major mental disorders in Han Chinese population. World J Biol Psychiatry 2021; 22:526-534. [PMID: 33143498 DOI: 10.1080/15622975.2020.1845793] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/21/2020] [Accepted: 10/28/2020] [Indexed: 10/24/2022]
Abstract
OBJECTIVES Environmental and genetic factors play important roles in the development of schizophrenia (SCZ), bipolar disorder (BPD) or major depressive disorder (MDD). Some risk loci are identified with shared genetic effects on major psychiatric disorders. To investigate whether SNX29 gene played a significant role in these psychiatric disorders in the Han Chinese population. METHODS We focussed on 11 single-nucleotide polymorphisms (SNPs) harbouring SNX29 gene and carried out case-control studies in patients with SCZ (n = 1248), BPD (n = 1344), or MDD (n = 1056), and 1248 healthy controls (HC) recruited from the Han Chinese population. We constructed weighted gene co-expression network analysis (WGCNA) and extracted significant modules by R package. RESULTS We found that rs3743592 was significantly associated with MDD and rs6498263 with BPD in both allele and genotype distributions. Before correction, rs3743592 showed allelic and genotypic significance with SCZ, rs6498263 showed allelic significance with SCZ. WGCNA identified top 10 modules of co-expressed genes. Gene Ontology (GO) and pathway analysis were used to examine the functions of SNX29, which revealed that SNX29 was involved in the regulation of a number of biological processes, such as TGF-beta, ErbB, and Wnt signalling pathway, etc. CONCLUSIONS Our results supported common risk factors in SNX29 might share among these three mental disorders in the Han Chinese population.
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Affiliation(s)
- Jian-Hua Chen
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, P. R. China
| | - Ying Zhao
- Physical Education Department, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Raja Amjad Waheed Khan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
- Department of Chemistry, University of Azad Jammu and Kashmir, Muzaffarabad, Pakistan
| | - Zhi-Qiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
- Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, P. R. China
- The Affiliated Hospital of Qingdao University and The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, P. R. China
| | - Juan Zhou
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Jia-Wei Shen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Si-Ying Xiang
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Ning-Ning Li
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Zu-Jia Wen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Xue-Min Jian
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Zhi-Jian Song
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Robert Stewart
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- South London and Maudsley NHS Foundation Trust, London, UK
| | - Zhuo Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Dun Pan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
| | - Yi-Feng Xu
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Yong-Yong Shi
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P. R. China
- Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, P. R. China
- The Affiliated Hospital of Qingdao University and The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, P. R. China
- Shanghai Changning Mental Health Center, Shanghai, P. R. China
- Department of Psychiatry, The First Teaching Hospital of Xinjiang Medical University, Urumqi, P. R. China
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Chen Q, Li D, Jin W, Shi Y, Li Z, Ma P, Sun J, Chen S, Li P, Lin P. Research Progress on the Correlation Between Epigenetics and Schizophrenia. Front Neurosci 2021; 15:688727. [PMID: 34366776 PMCID: PMC8334178 DOI: 10.3389/fnins.2021.688727] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/03/2021] [Indexed: 11/13/2022] Open
Abstract
Purpose of the Review Nowadays, the incidence of schizophrenia is noticeably increased. If left undiagnosed and untreated, it will lead to impaired social functions, repeated hospital admissions, decline in quality of life and life expectancy. However, the diagnosis of schizophrenia is complicated and challenging. Both genetic and environmental factors are considered as important contributors to the development and progression of this disorder. The environmental factors have been linked to changes in gene expression through epigenetic modulations, which have raised more and more research interests in recent years. This review article is to summarize the current findings and understanding of epigenetic modulation associated with pathogenesis of schizophrenia, aiming to provide useful information for further research in developing biomarkers for schizophrenia. Recent Findings Three major types of epigenetic modulations have been described in this article. Firstly, both DNA hypermethylation and hypomethylated have been associated with schizophrenia via analyzing post-mortem brain tissues and peripheral blood of patients. Specific changes of non-coding RNAs, particularly microRNAs and long-chain non-coding RNAs, have been observed in central and peripheral samples of schizophrenia patients, indicating their significant diagnostic value for the disease, and may also potentially predict treatment response. The correlation between histone modification and schizophrenia, however, is largely unclear. Summary Epigenetic modulations, including DNA methylation, ncRNA transcriptional regulation and histone modification, play an important role in the pathogenesis of schizophrenia. Therefore, tests of these epigenetic alterations may be utilized to assist in the diagnosis and determination of strategies of individualized treatment in clinical practice.
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Affiliation(s)
- Qing Chen
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Li
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weifeng Jin
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Shi
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenhua Li
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peijun Ma
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaqi Sun
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuzi Chen
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Li
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Lin
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Yao H, Guan L, Zhang C, Pan Y, Han J, He R, Chang Z, Zhou T, Du C, Wu T, Sun J, Yuan Y, Maybery D, Ma H. Chinese mental health workers' family-focused practices: a cross-sectional survey. BMC Health Serv Res 2021; 21:569. [PMID: 34107937 PMCID: PMC8191031 DOI: 10.1186/s12913-021-06572-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/21/2021] [Indexed: 11/26/2022] Open
Abstract
Background Mental disorders impose heavy burdens on patients’ families and children. It is imperative to provide family-focused services to avoid adverse effects from mental disorders on patients’ families and children. However, implementing such services requires a great deal of involvement of mental health workers. This study investigated the attitudes, knowledge, skills, and practices in respect to family-focused practices (FFP) in a sample of Chinese mental health workers. Methods A cross-sectional study design was employed to examine the attitudes, knowledge, skills, and practices of a convenience sample of Chinese mental health workers in respect to FFP, using the Chinese version of the Family-Focused Mental Health Practice Questionnaire (FFMHPQ). Results In total, 515 mental health workers participated in our study, including 213 psychiatrists, 269 psychiatric nurses, and 34 allied mental health professionals (20 clinical psychologists, 9 mental health social workers, and 4 occupational therapists). Compared with psychiatric nurses, psychiatrists and allied mental health professionals provided more support for families and children of patients with mental illness and were more willing to receive further training in FFP. However, there were no significant differences on knowledge, skills, and confidence across different profession types. After adjusting for demographic and occupational variables, previous training in FFP was positively associated with mental health workers’ knowledge, skills, and confidence about FFP, but not actual support to families and children. Conclusions Professional differences on FFP exist in Chinese mental health workers. Training is needed to engage psychiatrists and other allied workforce in dissemination and implementation of FFP in China.
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Affiliation(s)
- Hao Yao
- Harvard T. H. Chan School of Public Health, Boston, MA, USA.,Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lili Guan
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China.
| | - Changchun Zhang
- Fangshan District Mental Health Care Hospital, Beijing, China
| | - Yang Pan
- Fangshan District Mental Health Care Hospital, Beijing, China
| | - Jinxiang Han
- Beijing Xicheng District Ping'an Hospital, Beijing, China
| | - Rui He
- Mental Health Prevention Hospital of Haidian District, Beijing, China
| | - Zhengjiao Chang
- Mental Health Prevention Hospital of Haidian District, Beijing, China
| | - Tianhang Zhou
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Chunyu Du
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Tingfang Wu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Jingwen Sun
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Yilin Yuan
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Darryl Maybery
- Department of Rural Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, 15 Sargeant Street, 3820, Warragul, Victoria, Australia
| | - Hong Ma
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
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Chen J, Yang P, Zhang Q, Chen R, Wang P, Liu B, Sun W, Jian X, Xiang S, Zhou J, Li N, Wang K, Gao C, Wen Y, Wu C, Zhang J, Zhao Y, Yang Q, Li M, Stewart R, Sun Y, Pan D, Niu Y, Wang Z, Xu Y, Li X, He L, Li Z, Shi Y. Genetic risk of clozapine-induced leukopenia and neutropenia: a genome-wide association study. Transl Psychiatry 2021; 11:343. [PMID: 34083506 PMCID: PMC8175348 DOI: 10.1038/s41398-021-01470-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/20/2021] [Accepted: 05/06/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). METHODS A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). RESULTS The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10-8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10-8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. CONCLUSIONS The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.
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Affiliation(s)
- Jianhua Chen
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China.
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China.
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China.
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 8AF, United Kingdom.
| | - Ping Yang
- Wuhu Fourth People's Hospital, Wuhu, 242407, PR China
| | - Qian Zhang
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China
| | - Ruirui Chen
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China
| | - Peng Wang
- Wuhu Fourth People's Hospital, Wuhu, 242407, PR China
| | - Benxiu Liu
- Longquan Mountain Hospital of Guangxi Province, Liuzhou, 545005, PR China
| | - Wensheng Sun
- Longquan Mountain Hospital of Guangxi Province, Liuzhou, 545005, PR China
| | - Xuemin Jian
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Siying Xiang
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China
| | - Juan Zhou
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Ningning Li
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China
| | - Ke Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Chengwen Gao
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China
| | - Yanqin Wen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Chuanhong Wu
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China
| | - Jinmai Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Yalin Zhao
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China
| | - Qiangzhen Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Meihang Li
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China
| | - Robert Stewart
- Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, SE5 8AF, United Kingdom
- South London and Maudsley NHS Foundation Trust, London, UK
| | - Yuanchao Sun
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China
| | - Dun Pan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Yujuan Niu
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China
| | - Zhuo Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Yifeng Xu
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China
| | - Xingwang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China
| | - Zhiqiang Li
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China.
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China.
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China.
- Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, 200030, PR China.
| | - Yongyong Shi
- The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, 266003, PR China.
- Shanghai Clinical Research Center for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China.
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, 200030, PR China.
- Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, 200030, PR China.
- Shanghai Changning Mental Health Center, 299 Xiehe Road, Shanghai, 200042, PR China.
- Department of Psychiatry, The First Teaching Hospital of Xinjiang Medical University, Urumqi, 830054, PR China.
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Abstract
OBJECTIVE Bipolar disorder (BD) is a chronic mental health disorder with significant morbidity and mortality. Age at onset (AAO) may be a key variable in delineating more homogeneous subgroups of BD patients. However, no known research has systematically assessed how BD age-at-onset subgroups should be defined. METHODS We systematically searched the following databases: Cochrane Central Register of Controlled Trials, PsycINFO, MEDLINE, Embase, CINAHL, Scopus, Proquest Dissertations and Theses, Google Scholar and BIOSIS Previews. Original quantitative English language studies investigating AAO in BD were sought. RESULTS A total of 9454 unique publications were identified. Twenty-one of these were included in data analysis (n = 22981 BD participants). Fourteen of these studies (67%, n = 13626 participants) found a trimodal AAO distribution: early-onset (µ = 17.3, σ = 1.19, 45% of sample), mid-onset (µ = 26.0, σ = 1.72, 35%), and late-onset (µ = 41.9, σ = 6.16, 20%). Five studies (24%, n = 1422 participants) described a bimodal AAO distribution: early-onset (µ = 24.3, σ = 6.57, 66% of sample) and late-onset (µ = 46.3, σ = 14.15, 34%). Two studies investigated cohort effects on BD AAO and found that when the sample was not split by cohort, a trimodal AAO was the winning model, but when separated by cohort a bimodal distribution fit the data better. CONCLUSIONS We propose that the field conceptualises bipolar disorder age-at-onset subgroups as referring broadly to life stages. Demarcating BD AAO groups can inform treatment and provide a framework for future research to continue to investigate potential mechanisms of disease onset.
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Affiliation(s)
- Sorcha Bolton
- Department of PsychiatryUniversity of OxfordWarneford HospitalOxfordUK
| | - Jeremy Warner
- University of Oxford Medical SchoolJohn Radcliffe HospitalOxfordUK
| | - Eli Harriss
- Bodleian Health Care LibrariesUniversity of OxfordOxfordUK
| | - John Geddes
- Department of PsychiatryUniversity of OxfordWarneford HospitalOxfordUK,Oxford Health NHS Foundation TrustWarneford HospitalOxfordUK
| | - Kate E. A. Saunders
- Department of PsychiatryUniversity of OxfordWarneford HospitalOxfordUK,Oxford Health NHS Foundation TrustWarneford HospitalOxfordUK
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Martynikhin IA. The Use of ICD-10 for Diagnosing Mental Disorders In Russia, According to National Statistics and a Survey of Psychiatrists' Experience. CONSORTIUM PSYCHIATRICUM 2021; 2:35-44. [PMID: 39070732 PMCID: PMC11272308 DOI: 10.17816/cp69] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 03/15/2021] [Indexed: 12/27/2022] Open
Abstract
Purpose and methods In order to assess the specifics of practical use of the ICD-10 Diagnostic Guidelines by Russian psychiatrists, official national statistics on the prevalence of a number of mental disorders in Russia in 2019 were compared with the results of meta-analyses of international epidemiological studies of these disorders. In addition, a number of items in the online psychiatrists' survey, relating to the diagnosis of schizophrenia, were analysed; 807 Russian psychiatrists took part in the online survey. Results Analysis of national statistics showed that domestic clinicians diagnose some mental disorders significantly less often than might be expected, according to data obtained by international epidemiological studies. The number of cases of bipolar affective disorder registered in Russia is 90-150 times less than that for the prevalence of this disorder, according to meta-analyses of epidemiological studies; for depression, the result is 50-70 times; for anxiety disorders, the number is 25-50 times, and for autism, it is 30 times. Instead of the above disorders, diagnoses of organic non-psychotic mental disorders and schizophrenia might have been used unreasonably often. Between 2005 and 2019, diagnosis of childhood autism changed significantly (an increase of more than 100%), while the frequency of diagnosing other mental disorders remained unchanged. The results of the online survey also showed largely perfunctory use of the ICD-10 Diagnostic Guidelines, with a third of respondents reporting never checking the diagnostic schedules, and another third doing so from time to time. In addition, the low estimates given by survey participants regarding practical utility of the ICD-10 Diagnostic Guidelines, along with a large percentage of respondents who do not directly use diagnostic criteria in their work, indicate the need to improve the clinical usefulness of the diagnostic guidelines in the latest revision of the ICD, including convenience of use in practice. Conclusion The results of analysis of the Russian national mental health service statistic indicate that at least some diagnostic categories are not used by Russian psychiatrists exactly as ICD-10 suggests. The revealed discrepancy between the principles of diagnostics observed by domestic clinicians and international criteria may interfere with the use of evidence-based treatment algorithms, negatively affecting the quality of psychiatric care. In light of the upcoming transition to ICD-11 and in order to unify approaches to the diagnosis of mental disorders in our country, it is necessary to update and improve educational programmes for psychiatrists.
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Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population. Transl Psychiatry 2021; 11:301. [PMID: 34016946 PMCID: PMC8137921 DOI: 10.1038/s41398-021-01407-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 04/05/2021] [Accepted: 04/21/2021] [Indexed: 02/04/2023] Open
Abstract
The search for susceptibility genes underlying the heterogeneous bipolar disorder has been inconclusive, often with irreproducible results. There is a hope that narrowing the phenotypes will increase the power of genetic analysis. Early-onset bipolar disorder is thought to be a genetically homogeneous subtype with greater symptom severity. We conducted a genome-wide association study (GWAS) for this subtype in bipolar I (BPI) disorder. Study participants included 1779 patients of Han Chinese descent with BPI disorder recruited by the Taiwan Bipolar Consortium. We conducted phenotype assessment using the Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry and prepared a life chart with graphic depiction of lifetime clinical course for each of the BPI patient recruited. The assessment of onset age was based on this life chart with early onset defined as ≤20 years of age. We performed GWAS in a discovery group of 516 early-onset and 790 non-early-onset BPI patients, followed by a replication study in an independent group of 153 early-onset and 320 non-early-onset BPI patients and a meta-analysis with these two groups. The SNP rs11127876, located in the intron of CADM2, showed association with early-onset BPI in the discovery cohort (P = 7.04 × 10-8) and in the test of replication (P = 0.0354). After meta-analysis, this SNP was demonstrated to be a new genetic locus in CADM2 gene associated with early-onset BPI disorder (P = 5.19 × 10-8).
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Ijichi S, Kawaike Y, Ijichi N, Ijichi Y, Hirakata M, Yamaguchi Y, Kamachi A, Imamura C, Fushuku S, Nagata J, Tanuma R, Sameshima H, Morioka H. Hypothetical novel simulations to explain the evolutionary survival of the hypo-reproductive extreme tail in the complex human diversity. Biosystems 2021; 204:104393. [PMID: 33640397 DOI: 10.1016/j.biosystems.2021.104393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 02/20/2021] [Indexed: 10/22/2022]
Abstract
Hierarchical structures which lie hidden between human complex conditions and reproductivity cannot be simple, and trends of each population component does not necessarily pertain to evolutionary theories. As an illustration, the fitness of individuals with heritable extreme conditions can be low across continuing generations in observational data. Autism and schizophrenia are characterized by such evolutionary paradox of survival and hypo-reproductivity in the complex human diversity. Theoretical mechanisms for the observational fact were evaluated using a simple formula which was established to simulate stochastic epistasis-mediated phenotypic diversity. The survival of the hypo-reproductive extreme tail could be imitated just by the predominant presence of stochastic epistasis mechanism, suggesting that stochastic epistasis might be a genetic prerequisite for the evolutionary paradox. As supplemental cofactors of stochastic epistasis, a random link of the extreme tail to both un- and hyper-reproductivity and group assortative mating were shown to be effective for the paradox. Especially, the mixed localization of un- and hyper-reproductivity in the tail of a generational population evidently induced the continuous survival of outliers and extremes. These hypothetical considerations and mathematical simulations may suggest the significance of stochastic epistasis as the essential genetic background of complex human diversity.
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Affiliation(s)
- Shinji Ijichi
- Health Service Center, Kagoshima University, Kagoshima, Japan; Institute for Externalization of Gifts and Talents, Kagoshima, Japan.
| | - Yoichi Kawaike
- Health Service Center, Kagoshima University, Kagoshima, Japan
| | - Naomi Ijichi
- Institute for Externalization of Gifts and Talents, Kagoshima, Japan
| | - Yukina Ijichi
- Institute for Externalization of Gifts and Talents, Kagoshima, Japan
| | - Mai Hirakata
- Health Service Center, Kagoshima University, Kagoshima, Japan
| | - Yuka Yamaguchi
- Health Service Center, Kagoshima University, Kagoshima, Japan
| | - Akiyo Kamachi
- Health Service Center, Kagoshima University, Kagoshima, Japan
| | - Chikako Imamura
- Support Center for Students with Disabilities, Kagoshima University, Kagoshima, Japan
| | - Sayuri Fushuku
- Health Service Center, Kagoshima University, Kagoshima, Japan
| | - Junko Nagata
- Health Service Center, Kagoshima University, Kagoshima, Japan
| | - Rie Tanuma
- Health Service Center, Kagoshima University, Kagoshima, Japan
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Chen J, Chen R, Xiang S, Li N, Gao C, Wu C, Zhang Q, Zhao Y, Liao Y, Stewart R, Xu Y, Shi Y, Li Z. Cigarette smoking and schizophrenia: Mendelian randomisation study. Br J Psychiatry 2021; 218:98-103. [PMID: 32552923 DOI: 10.1192/bjp.2020.116] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND The link between schizophrenia and cigarette smoking has been well established through observational studies. However, the cause-effect relationship remains unclear. AIMS We conducted Mendelian randomisation analyses to assess any causal relationship between genetic variants related to four smoking-related traits and the risk of schizophrenia. METHOD We performed a two-sample Mendelian randomisation using summary statistics from genome-wide association studies (GWAS) of smoking-related traits and schizophrenia (7711 cases, 18 327 controls) in East Asian populations. Single nucleotide polymorphisms (SNPs) correlated with smoking behaviours (smoking initiation, smoking cessation, age at smoking initiation and quantity of smoking) were investigated in relation to schizophrenia using the inverse-variance weighted (IVW) method. Further sensitivity analyses, including Mendelian randomisation-Egger (MR-Egger), weighted median estimates and leave-one-out analysis, were used to test the consistency of the results. RESULTS The associated SNPs for the four smoking behaviours were not significantly associated with schizophrenia status. Pleiotropy did not inappropriately affect the results. CONCLUSIONS Cigarette smoking is a complex behaviour in people with schizophrenia. Understanding factors underlying the observed association remains important; however, our findings do not support a causal role of smoking in influencing risk of schizophrenia.
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Affiliation(s)
- Jianhua Chen
- Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao University; and Shanghai Clinical Research Centre for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine; and Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Centre for Brain Science, Shanghai Jiao Tong University, P. R. China; and Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
| | - Ruirui Chen
- Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao University, P. R. China
| | - Siying Xiang
- Shanghai Clinical Research Centre for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, P. R. China
| | - Ningning Li
- Shanghai Clinical Research Centre for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, P. R. China
| | - Chengwen Gao
- Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao University, P. R. China
| | - Chuanhong Wu
- Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao University, P. R. China
| | - Qian Zhang
- Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao University, P. R. China
| | - Yalin Zhao
- Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao University, P. R. China
| | - Yanhui Liao
- Department of Psychiatry, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, P. R. China
| | - Robert Stewart
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London; and South London and Maudsley NHS Foundation Trust, London, UK
| | - Yifeng Xu
- Shanghai Clinical Research Centre for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine, P. R. China
| | - Yongyong Shi
- Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao University; and Shanghai Clinical Research Centre for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine; and Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Centre for Brain Science, Shanghai Jiao Tong University; and Shanghai Key Laboratory of Sleep Disordered Breathing; and Shanghai Changning Mental Health Centre; and Department of Psychiatry, First Teaching Hospital of Xinjiang Medical University, Urumqi, P. R. China
| | - Zhiqiang Li
- Affiliated Hospital of Qingdao University & Biomedical Sciences Institute of Qingdao University, Qingdao University; and Shanghai Clinical Research Centre for Mental Health, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Centre, Shanghai Jiao Tong University School of Medicine; and Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Centre for Brain Science, Shanghai Jiao Tong University; and Shanghai Key Laboratory of Sleep Disordered Breathing, P. R. China
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Gualtieri CT. Genomic Variation, Evolvability, and the Paradox of Mental Illness. Front Psychiatry 2021; 11:593233. [PMID: 33551865 PMCID: PMC7859268 DOI: 10.3389/fpsyt.2020.593233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/27/2020] [Indexed: 12/30/2022] Open
Abstract
Twentieth-century genetics was hard put to explain the irregular behavior of neuropsychiatric disorders. Autism and schizophrenia defy a principle of natural selection; they are highly heritable but associated with low reproductive success. Nevertheless, they persist. The genetic origins of such conditions are confounded by the problem of variable expression, that is, when a given genetic aberration can lead to any one of several distinct disorders. Also, autism and schizophrenia occur on a spectrum of severity, from mild and subclinical cases to the overt and disabling. Such irregularities reflect the problem of missing heritability; although hundreds of genes may be associated with autism or schizophrenia, together they account for only a small proportion of cases. Techniques for higher resolution, genomewide analysis have begun to illuminate the irregular and unpredictable behavior of the human genome. Thus, the origins of neuropsychiatric disorders in particular and complex disease in general have been illuminated. The human genome is characterized by a high degree of structural and behavioral variability: DNA content variation, epistasis, stochasticity in gene expression, and epigenetic changes. These elements have grown more complex as evolution scaled the phylogenetic tree. They are especially pertinent to brain development and function. Genomic variability is a window on the origins of complex disease, neuropsychiatric disorders, and neurodevelopmental disorders in particular. Genomic variability, as it happens, is also the fuel of evolvability. The genomic events that presided over the evolution of the primate and hominid lineages are over-represented in patients with autism and schizophrenia, as well as intellectual disability and epilepsy. That the special qualities of the human genome that drove evolution might, in some way, contribute to neuropsychiatric disorders is a matter of no little interest.
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Su Y, Yang L, Li Z, Wang W, Xing M, Fang Y, Cheng Y, Lin GN, Cui D. The interaction of ASAH1 and NGF gene involving in neurotrophin signaling pathway contributes to schizophrenia susceptibility and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 2021; 104:110015. [PMID: 32569620 DOI: 10.1016/j.pnpbp.2020.110015] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 05/23/2020] [Accepted: 06/09/2020] [Indexed: 02/07/2023]
Abstract
The neurodevelopmental hypothesis of schizophrenia has been widely accepted. In light of our previous microarray data, two neurodevelopment-related genes were focused on inclduing the N-acylsphingosine amidohydrolase 1 gene (ASAH1) and the nerve growth factor gene (NGF). The evidence that ASAH1 and NGF are associated with schizophrenia is far from conclusive. Furthermore, their interactions in schizophrenia have not been investigated. Total 413 patients and 578 controls were included. Eleven single-nucleotide polymorphisms (SNPs) in ASAH1 and NGF were selected. A multifactor dimensionality reduction (MDR) was applied to investigate gene-gene interactions in schizophrenia, and the traditional odds ratio methods was applied to validate it. The effects of ASAH1, NGF and their interaction on the severity of the disease were analyzed by 3 × 3 covariance analysis of (ANCOVA). The biological interaction between ASAH1 and NGF was examined. KEGG was used to identify the related signaling pathways. After correction by Bonferroni, there were no differences in the genotypic, allelic, or haplotypic frequencies of 11 SNPs between patients and controls. However, the interaction of certain SNPs had effect on susceptibility to schizophrenia, including two high-risk and one low-risk genotypic combinations (OR = 1.49 [1.11-2.00]; OR = 1.45 [1.09-1.92], and OR = 0.64 [0.41-0.98]). ASAH1-rs7830490 and its interaction with NGF-rs4332358 were associated with the general psychopathological subscale score (F adjusted = 3.94, p adjusted = 0.01; F adjusted = 2.36, p adjusted = 0.03). We also found that ASAH1 and NGF interacted with CaMK2B involving in the neurotrophin signaling pathway. Our results suggest that the interaction of ASAH1 and NGF with CaMK2B involved in neurotrophin signaling pathway may contribute to schizophrenia susceptibility and psychopathology.
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Affiliation(s)
- Yousong Su
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Yang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zezhi Li
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Weidi Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - Mengjuan Xing
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; Key Laboratory of Translational Psychiatry, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Fang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; Key Laboratory of Translational Psychiatry, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Cheng
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; Key Laboratory of Translational Psychiatry, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guan Ning Lin
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - Donghong Cui
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; Key Laboratory of Translational Psychiatry, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
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Hederih J, Nuninga JO, van Eijk K, van Dellen E, Smit DJA, Oranje B, Luykx JJ. Genetic underpinnings of schizophrenia-related electroencephalographical intermediate phenotypes: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2021; 104:110001. [PMID: 32525059 DOI: 10.1016/j.pnpbp.2020.110001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/02/2020] [Accepted: 06/03/2020] [Indexed: 02/04/2023]
Abstract
Although substantial research into genetics of psychotic disorders has been conducted, a large proportion of their genetic architecture has remained unresolved. Electroencephalographical intermediate phenotypes (EIP) have the potential to constitute a valuable tool when studying genetic risk loci for schizophrenia, in particular P3b amplitude, P50 suppression, mismatch negativity (MMN) and resting state power spectra of the electroencephalogram (EEG). Here, we systematically reviewed studies investigating the association of single nucleotide polymorphisms (SNPs) with these EIPs and meta-analysed them when appropriate. We retrieved 45 studies (N = 34,971 study participants). Four SNPs investigated in more than one study were genome-wide significant for an association with schizophrenia and three were genome-wide suggestive, based on a lookup in the influential 2014 GWAS (Ripke et al., 2014). However, in our meta-analyses, rs1625579 failed to reach a statistically significant association with p3b amplitude decrease and rs4680 risk allele carrier status was not associated with p3b amplitude decrease or with impaired p50 suppression. In conclusion, evidence for SNP associations with EIPs remains limited to individual studies. Careful selection of EIPs and SNPs, combined with consistent reporting of effect sizes, directions of effect and p-values would aid future meta-analyses.
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Affiliation(s)
- Jure Hederih
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, CX 3584, the Netherlands; Medical Sciences Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
| | - Jasper O Nuninga
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, CX 3584, the Netherlands
| | - Kristel van Eijk
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, CX 3584, the Netherlands
| | - Edwin van Dellen
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, CX 3584, the Netherlands; Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia
| | - Dirk J A Smit
- Department of Psychiatry, Academic Medical Centre, Meibergdreef 5, Amsterdam 1105 AZ, the Netherlands
| | - Bob Oranje
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, CX 3584, the Netherlands
| | - Jurjen J Luykx
- Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, CX 3584, the Netherlands; Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, CX 3584, the Netherlands; GGNet Mental Health, Apeldoorn, the Netherlands
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Dysregulation of miR-185, miR-193a, and miR-450a in the skin are linked to the depressive phenotype. Prog Neuropsychopharmacol Biol Psychiatry 2021; 104:110052. [PMID: 32738353 DOI: 10.1016/j.pnpbp.2020.110052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/23/2020] [Accepted: 07/26/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND Dysregulated microRNAs (miRNAs) in dermal fibroblasts of depressive subjects, indicate biomarker potential and can possibly aid clinical diagnostics. To overcome methodological challenges related to human experiments and fibroblast cultures, we here validate 38 miRNAs previously observed to be dysregulated in human fibroblasts from depressed subjects, in the skin of four distinct rat models of depression. METHODS In the presented study male rats from the adrenocorticotropic hormone (ACTH) model (n = 10/group), the chronic mild stress model (n = 10/group), Wistar Kyoto/Wistar Hannover rats (n = 10/group), and Flinders Resistant/Flinders Sensitive Line rats (n = 8/group) were included. Real-time qPCR was utilized to investigate miRNA alterations in flash-frozen skin-biopsies from the ear and fibroblast cultures. RESULTS In the ACTH rat model of depression, we identified nine dysregulated miRNAs in the skin and three in the fibroblasts. As the skin presented three times the amount of dysregulated miRNAs compared to the fibroblasts, skin instead of fibroblasts were continuously used for studies with the other rat models. In the skin from the four rat models of depression, 15 out of 38 miRNAs re-exhibited significant dysregulation in at least one of the rat models of depression and 67% were regulated in the same direction as in the human study. miR-450a and miR-193a presented dysregulation across rat models and miR-193a and miR-185 exhibited very strong dysregulation (30-fold and 50-fold, respectively). Lastly, an Ingenuity Pathway Analysis indicated functional overlap between dysregulated miRNAs, and common regulated pathways. CONCLUSION Flash-frozen skin is a valid alternative to fibroblast cultures as the skin appear to retain more of the miRNA dysregulation present in vivo. A sub-population of 15 miRNAs appear to be specific for the depressive phenotype, as they are dysregulated in both human depressed patients and distinct rat models of depression. We propose miR-450a, miR-185, and miR-193a as biomarker candidates of particular interest.
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Abstract
Stress system dysfunction is a typical characteristic of acute depression and other mood disorders. The exact pattern of factors predisposing for stress-related mental disorders is yet to be unraveled. However, corticosteroid receptor function plays an important role for appropriate or dysfunctional neuroendocrine responses to stress exposure and hence in resilience or risk for the development and course of both, depression and anxiety disorders. Solid neuroscience data strongly support that both neuropeptides, corticotropin-releasing hormone (CRH) and vasopressin (AVP), are central in coordinating humoral and behavioral adaptation to stress. Other neuropeptides, including oxytocin, neuropeptide S, neuropeptide Y, and orexin, are also considered important contributors. Attempts to turn neuropeptide biology into treatments for stress-related disorders need to consider that neuropeptide receptors are specific drug targets for certain patient populations rather than universal targets for all patients, like biogenic amine systems. That is why most negative clinical trials testing neuropeptide receptor antagonists have been in fact failed trials by design, because no companion tests were used to identify which patients with depression are most likely to benefit from a specific neuropeptide receptor-targeting drug treatment. Therefore, the most important future research task is discovery and development of appropriate companion tests that will allow the successful transfer of the precious treasure of neuropeptide system-targeting drugs into clinics.
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Affiliation(s)
| | - Marcus Ising
- Max Planck Institute of Psychiatry, Munich, Germany
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Common variants in FAN1, located in 15q13.3, confer risk for schizophrenia and bipolar disorder in Han Chinese. Prog Neuropsychopharmacol Biol Psychiatry 2020; 103:109973. [PMID: 32450113 DOI: 10.1016/j.pnpbp.2020.109973] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 01/01/2023]
Abstract
Multiple genetic risk factors have been associated with psychiatric disorders which provides the genetic insight to these disorders; however, the etiology of these disorders is still elusive. 15q13.3 was previously associated with schizophrenia, bipolar and other neurodevelopmental disorders. Whereas, the FAN1 which encodes the Fanconi anemia associated nuclease 1 was suggested to be causal gene for 15q13.3 related psychiatric disorders. This study aimed to investigate the association of FAN1 with three major psychiatric disorders. Herein, we conducted a case-control study with the Chinese Han population. Three single nucleotide polymorphisms (SNPs) of FAN1 were genotyped in 1248 schizophrenia cases, 1344 bipolar disorder cases, 1056 major depressive disorder cases and 1248 normal controls. We found that SNPs rs7171212 was associated with bipolar (pallele = 0.023, pgenotype = 0.022, OR = 0.658) and schizophrenia (pallele = 0.021, pgenotype = 0.019, OR = 0.645). Whereas, rs4779796 was associated with schizophrenia (pgenotype = 0.001, adjusted pgenotype = 0.003, OR = 1.089). In addition, rs7171212 (adjusted pallele = 0.018, adjusted pgenotype = 0.018, OR = 0.652) and rs4779796 (adjusted pgenotype = 0.024, OR = 1.12) showed significantly associated with combined cases of schizophrenia and bipolar disorder. Further, meta-analysis was performed with the case-control data and dataset extracted from previously reported genome-wide association study to validate the promising SNPs. Our results provide the new evidence that FAN1 may be a common susceptibility gene for schizophrenia and bipolar disorder in Han Chinese. These novel findings need further validation with larger sample size and functional characterization to understand the underlying pathogenic mechanism behind FAN1 in the prevalence of schizophrenia and bipolar disorders.
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Identification of a functional SNP rs7304782 at schizophrenia risk locus 12q24.31 and validation of its association with schiz ophrenia in Chinese populations. Psychiatry Res 2020; 294:113491. [PMID: 33070109 DOI: 10.1016/j.psychres.2020.113491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/28/2020] [Indexed: 12/19/2022]
Abstract
Recent genome-wide association studies (GWAS) have identified multiple schizophrenia-associated risk loci. However, the potential functional (or causal) variant remains largely unknown for each of the identified risk locus. In this study, we utilized different functional annotation approaches (i.e., CADD, Eigen, GWAVA, RegulomeDB and LINSIGHT) to prioritize the most possible functional variant at schizophrenia risk locus 12q24.31, a risk locus that showed genome-wide significant association with schizophrenia. We found that four functional annotation methods prioritized rs7304782 as a potential functional variant at 12q24.31, suggesting the potential functional consequence of rs7304782. Consistent with the functional annotation, reporter gene assays showed that different allele of rs7304782 affected the luciferase activity significantly, further supporting that rs7304782 is a functional variant. We further performed genetic association study and validated that rs7304782 is also associated with schizophrenia in Chinese population (N=4,291 cases and 7,847 controls), with the same risk allele as in European population. Expression quantitative trait loci (eQTL) analysis indicated that rs7304782 was significantly associated with the expression of OGFOD2 in human brain tissues. Of note, differential expression analysis indicated that OGFOD2 was significantly down-regulated in schizophrenia cases compared with controls. Our study identified a potential functional variant (i.e., rs7304782) at schizophrenia risk locus 12q24.31 and suggested that this functional variant may confer schizophrenia risk through regulating OGFOD2 expression.
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Abdoli A, Taghipour A, Pirestani M, Mofazzal Jahromi MA, Roustazadeh A, Mir H, Ardakani HM, Kenarkoohi A, Falahi S, Karimi M. Infections, inflammation, and risk of neuropsychiatric disorders: the neglected role of "co-infection". Heliyon 2020; 6:e05645. [PMID: 33319101 PMCID: PMC7725732 DOI: 10.1016/j.heliyon.2020.e05645] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/18/2020] [Accepted: 11/30/2020] [Indexed: 02/08/2023] Open
Abstract
Neuropsychiatric disorders (NPDs) have multiple etiological factors, mainly genetic background, environmental conditions and immunological factors. The host immune responses play a pivotal role in various physiological and pathophysiological process. In NPDs, inflammatory immune responses have shown to be involved in diseases severity and treatment outcome. Inflammatory cytokines and chemokines are involved in various neurobiological pathways, such as GABAergic signaling and neurotransmitter synthesis. Infectious agents are among the major amplifier of inflammatory reactions, hence, have an indirect role in the pathogenesis of NPDs. As such, some infections directly affect the central nervous system (CNS) and alter the genes that involved in neurobiological pathways and NPDs. Interestingly, the most of infectious agents that involved in NPDs (e.g., Toxoplasma gondii, cytomegalovirus and herpes simplex virus) is latent (asymptomatic) and co-or-multiple infection of them are common. Nonetheless, the role of co-or-multiple infection in the pathogenesis of NPDs has not deeply investigated. Evidences indicate that co-or-multiple infection synergically augment the level of inflammatory reactions and have more severe outcomes than single infection. Hence, it is plausible that co-or-multiple infections can increase the risk and/or pathogenesis of NPDs. Further understanding about the role of co-or-multiple infections can offer new insights about the etiology, treatment and prevention of NPDs. Likewise, therapy based on anti-infective and anti-inflammatory agents could be a promising therapeutic option as an adjuvant for treatment of NPDs.
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Affiliation(s)
- Amir Abdoli
- Department of Parasitology and Mycology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
- Zoonoses Research Center, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Ali Taghipour
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Majid Pirestani
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mirza Ali Mofazzal Jahromi
- Department of Advanced Medical Sciences & Technologies, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
- Department of Laboratory Sciences, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
- Research Center for Noncommunicable Diseases, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Abazar Roustazadeh
- Department of Advanced Medical Sciences & Technologies, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
- Research Center for Noncommunicable Diseases, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
- Department of Clinical Biochemistry, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Hamed Mir
- Research Center for Noncommunicable Diseases, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
- Department of Clinical Biochemistry, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Hoda Mirzaian Ardakani
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Azra Kenarkoohi
- Department of Microbiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Shahab Falahi
- Zoonotic Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Mahdi Karimi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Advances Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran, Iran
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Badcock PB, Moore E, Williamson E, Berk M, Williams LJ, Bjerkeset O, Nordahl HM, Patton GC, Olsson CA. Modeling gene‐environment interaction in longitudinal data: Risk for neuroticism due to interaction between maternal care and the Dopamine 4 Receptor gene (DRD4). AUSTRALIAN JOURNAL OF PSYCHOLOGY 2020. [DOI: 10.1111/j.1742-9536.2011.00003.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Paul B. Badcock
- Department of Paediatrics, The University of Melbourne, Melbourne
| | - Elya Moore
- Microbiology and Infectious Diseases Department, Royal Women's Hospital, Melbourne
| | - Elizabeth Williamson
- Centre for Molecular, Environmental, Genetic & Analytic Epidemiology, Melbourne School of Population Health Parkville, and the Department of Epidemiology and Preventive Medicine, Monash University, Melbourne
| | - Michael Berk
- Department of Clinical and Biomedical Sciences: Barwon Health, The University of Melbourne, Geelong, Victoria, Australia
| | - Lana J. Williams
- Centre for Molecular, Environmental, Genetic & Analytic Epidemiology, Melbourne School of Population Health Parkville, and the Department of Epidemiology and Preventive Medicine, Monash University, Melbourne
| | - Ottar Bjerkeset
- Department of Neuromedicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim
- Department of Research and Development, Levanger Hospital, Nord‐Trøndelag Health Trust
| | - Hans M. Nordahl
- Department of Psychology, Norwegian University of Science and Technology, Trondheim
- Department of Psychiatry, Levanger Hospital, Nord‐Trøndelag Health Trust, Norway
| | - George C. Patton
- Department of Paediatrics, The University of Melbourne, Melbourne
- Centre for Adolescent Health, Murdoch Childrens Research Institute, Royal Childrens Hospital, Melbourne
| | - Craig A. Olsson
- Department of Paediatrics, The University of Melbourne, Melbourne
- Centre for Adolescent Health, Murdoch Childrens Research Institute, Royal Childrens Hospital, Melbourne
- Psychological Sciences, The University of Melbourne, Melbourne, Victoria, Australia
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48
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Van eekelen JAM, Olsson CA, Ellis JA, Ang W, Hutchinson D, Zubrick SR, Pennell CE. Identification and genetic determination of an early life risk disposition for depressive disorder: Atypical stress‐related behaviour in early childhood. AUSTRALIAN JOURNAL OF PSYCHOLOGY 2020. [DOI: 10.1111/j.1742-9536.2011.00002.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- J. Anke M. Van eekelen
- Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, Western Australia
| | - Craig A. Olsson
- Murdoch Children's Research Institute, Royal Childrens Hospital and the University of Melbourne (Psychological Sciences & Department of Paediatrics), Melbourne, Victoria
| | - Justine A. Ellis
- Environmental & Genetic Epidemiology Research, Murdoch Childrens Research Institute, The Royal Childrens Hospital, Melbourne, Victoria
| | - Wei Ang
- The School of Women's and Infants' Health, University of Western Australia at King Edward Memorial Hospital, Perth, Western Australia
| | - Delyse Hutchinson
- National Drug and Alcohol Research Centre (NDARC), University of New South Wales, Sydney, New South Wales
| | - Stephen R. Zubrick
- Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, Western Australia
- Centre for Developmental Health, Curtin University of Technology, Perth, Western Australia, Australia
| | - Craig E. Pennell
- The School of Women's and Infants' Health, University of Western Australia at King Edward Memorial Hospital, Perth, Western Australia
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49
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Karmakar A, Bhattacharya M, Adhya J, Chatterjee S, Dogra AK. The trend of association between autism traits in mothers and severity of autism symptomatology in children. ADVANCES IN AUTISM 2020. [DOI: 10.1108/aia-01-2020-0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Purpose
Autism spectrum disorders (ASD) are heterogeneous disorders, and heterogeneity lies both at genetic and phenotypic levels. To better understand the etiology and pathway that may contribute to autism symptomatology, it is important to study milder expressions of autism characteristics – autistic traits or milder expressions of autism phenotype, especially in intergenerational context. This study aims to see the trend of association, if any, between child autism symptom and mothers’ autism phenotype as well as mothers’ theory of mind and to see if mothers’ theory of mind was associated with their own autistic traits.
Design/methodology/approach
Data were collected from 96 mothers of children with varying symptom severity of autism (mild, moderate and severe) using Autism Spectrum Quotient and faux pas recognition test. Analysis of variance, trend analysis and t-test were done.
Findings
Results showed a linear trend of relationship between mothers’ autism phenotype and child symptom severity. However, the groups did not have significant differences in theory of mind. Only a few components of theory of mind were found to be associated with autistic traits. These findings question the prevailing idea that theory of mind can be a reliable endophenotype of autism.
Research limitations/implications
There has been a lack of research assessing the possible link between parents’ autism phenotype and symptom severity of ASD children. This study is a preliminary step towards that direction. This study indicates a probability of shared genetic liability between mothers and offspring, which would have important consequences for understanding the mechanisms that lead to autism.
Practical implications
This study offers implications for treatment planning of those with clinical ASD. An awareness of parental factors is critical for any holistic intervention plan when a family seeks treatment for their child. This study suggests that while individualising interventions, clinicians may consider possible presence of high levels of autistic traits and related cognitive features present in the probands’ parents.
Originality/value
There has been lack of research assessing the possible link between parents’ autism phenotype and symptom severity of ASD children. This study, even though preliminary, is a step towards that direction. This study suggests that autism traits might be influenced by common genetic variation and indicates a probability of shared genetic liability between mothers and offspring, which would have important consequences for understanding the mechanisms that lead to autism.
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50
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Qing L, Liu L, Zhou L, Zhang F, Gao C, Hu L, Nie S. Sex-dependent association of mineralocorticoid receptor gene (NR3C2) DNA methylation and schizophrenia. Psychiatry Res 2020; 292:113318. [PMID: 32712448 DOI: 10.1016/j.psychres.2020.113318] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 07/07/2020] [Accepted: 07/19/2020] [Indexed: 12/20/2022]
Abstract
Schizophrenia is a complex disease caused by genetic and environmental factors. Epigenetic regulation mediates gene-environment interactions by modulating gene expression. Abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis has been widely reported in schizophrenia patients. The DNA methylation levels of critical genes are associated with HPA axis activity, which is linked to schizophrenia pathogenesis. The mineralocorticoid receptor gene NR3C2 regulates HPA axis activity. However, how NR3C2 methylation affects the development of schizophrenia remains unknown. Here, we investigated the DNA methylation state of NR3C2, including the promoter P1 (NR3C2-1, NR3C2-2 and NR3C2-3) and exon 1α and its downstream sequence (NR3C2-4), in schizophrenia. Peripheral blood DNA from 80 schizophrenia patients and 128 healthy controls was used to assess NR3C2 DNA methylation via sodium bisulfite treatment and the MethylTarget method. NR3C2-4 region was hypermethylated in schizophrenia patients compared with healthy controls in the female group. Specific CpG sites in P1 and NR3C2-4 region were associated with schizophrenia, with sex-specific effects. These findings showed a relationship between NR3C2 DNA methylation and schizophrenia, revealing that epigenetic processes may mediate schizophrenia pathophysiology. Further research should address the potential epigenetic mechanisms of the relationship between NR3C2 and schizophrenia.
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Affiliation(s)
- Lili Qing
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, People's Republc of China
| | - Linlin Liu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, People's Republc of China
| | - Li Zhou
- Mental Health Center of Yunnan Province, Kunming, Yunnan Province, People's Republc of China
| | - Fan Zhang
- Mental Health Center of Yunnan Province, Kunming, Yunnan Province, People's Republc of China
| | - Changqing Gao
- Mental Health Center of Yunnan Province, Kunming, Yunnan Province, People's Republc of China.
| | - Liping Hu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, People's Republc of China.
| | - Shengjie Nie
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan Province, People's Republc of China.
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