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Chbeir S, Carrión V. Resilience by design: How nature, nurture, environment, and microbiome mitigate stress and allostatic load. World J Psychiatry 2023; 13:144-159. [PMID: 37303926 PMCID: PMC10251360 DOI: 10.5498/wjp.v13.i5.144] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/11/2023] [Accepted: 04/17/2023] [Indexed: 05/19/2023] Open
Abstract
Resilience to psychological stress is defined as adaption to challenging life experiences and not the absence of adverse life events. Determinants of resilience include personality traits, genetic/epigenetic modifications of genes involved in the stress response, cognitive and behavioral flexibility, secure attachment with a caregiver, social and community support systems, nutrition and exercise, and alignment of circadian rhythm to the natural light/dark cycle. Therefore, resilience is a dynamic and flexible process that continually evolves by the intersection of different domains in human’s life; biological, social, and psychological. The objective of this minireview is to summarize the existing knowledge about the multitude factors and molecular alterations that result from resilience to stress response. Given the multiple contributing factors in building resilience, we set out a goal to identify which factors were most supportive of a causal role by the current literature. We focused on resilience-related molecular alterations resulting from mind-body homeostasis in connection with psychosocial and environmental factors. We conclude that there is no one causal factor that differentiates a resilient person from a vulnerable one. Instead, building resilience requires an intricate network of positive experiences and a healthy lifestyle that contribute to a balanced mind-body connection. Therefore, a holistic approach must be adopted in future research on stress response to address the multiple elements that promote resilience and prevent illnesses and psychopathology related to stress allostatic load.
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Affiliation(s)
- Souhad Chbeir
- Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA 94305, United States
| | - Victor Carrión
- Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA 94305, United States
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Hasan A, Afzal M. Gene and environment interplay in cognition: Evidence from twin and molecular studies, future directions and suggestions for effective candidate gene x environment (cGxE) research. Mult Scler Relat Disord 2019; 33:121-130. [PMID: 31185373 DOI: 10.1016/j.msard.2019.05.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 04/20/2019] [Accepted: 05/13/2019] [Indexed: 12/17/2022]
Abstract
Last decade of molecular research in the field of cognitive science has shown that no single approach can give satisfactory results as far as gene hunt is concerned. Cohesive theory of gene-environment interaction seems to be a rational idea for bridging the gap in our knowledge of disorders involving cognitive deficit. It may even be helpful to some extent in resolving issues of missing heritability. We review the current state of play in the area of cognition at genetic and environmental fronts. Evidence of apparent gene-environment (GxE) interactions from various studies has been mentioned with the aim of redirecting the focus of research community towards studying such interactions with the help of sensitive designs and molecular techniques. We re-evaluate candidate gene-environment research in order to emphasize its potential if carried out strategically.
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Affiliation(s)
- Anam Hasan
- Human Genetics and Toxicology Laboratory, Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, Uttar Pradesh, India
| | - Mohammad Afzal
- Human Genetics and Toxicology Laboratory, Section of Genetics, Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, Uttar Pradesh, India.
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3
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Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer's disease: the emerging role for microglia? Neurosci Biobehav Rev 2017; 77:148-164. [PMID: 28185874 DOI: 10.1016/j.neubiorev.2017.01.046] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 01/20/2017] [Accepted: 01/31/2017] [Indexed: 01/22/2023]
Abstract
Chronic psychosocial stress is increasingly recognized as a risk factor for late-onset Alzheimer's disease (LOAD) and associated cognitive deficits. Chronic stress also primes microglia and induces inflammatory responses in the adult brain, thereby compromising synapse-supportive roles of microglia and deteriorating cognitive functions during aging. Substantial evidence demonstrates that failure of microglia to clear abnormally accumulating amyloid-beta (Aβ) peptide contributes to neuroinflammation and neurodegeneration in AD. Moreover, genome-wide association studies have linked variants in several immune genes, such as TREM2 and CD33, the expression of which in the brain is restricted to microglia, with cognitive dysfunctions in LOAD. Thus, inflammation-promoting chronic stress may create a vicious cycle of aggravated microglial dysfunction accompanied by increased Aβ accumulation, collectively exacerbating neurodegeneration. Surprisingly, however, little is known about whether and how chronic stress contributes to microglia-mediated neuroinflammation that may underlie cognitive impairments in AD. This review aims to summarize the currently available clinical and preclinical data and outline potential molecular mechanisms linking stress, microglia and neurodegeneration, to foster future research in this field.
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Reynolds CA, Gatz M, Christensen K, Christiansen L, Dahl Aslan AK, Kaprio J, Korhonen T, Kremen WS, Krueger R, McGue M, Neiderhiser JM, Pedersen NL. Gene-Environment Interplay in Physical, Psychological, and Cognitive Domains in Mid to Late Adulthood: Is APOE a Variability Gene? Behav Genet 2016; 46:4-19. [PMID: 26538244 PMCID: PMC4858319 DOI: 10.1007/s10519-015-9761-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 10/14/2015] [Indexed: 10/22/2022]
Abstract
Despite emerging interest in gene-environment interaction (GxE) effects, there is a dearth of studies evaluating its potential relevance apart from specific hypothesized environments and biometrical variance trends. Using a monozygotic within-pair approach, we evaluated evidence of G×E for body mass index (BMI), depressive symptoms, and cognition (verbal, spatial, attention, working memory, perceptual speed) in twin studies from four countries. We also evaluated whether APOE is a 'variability gene' across these measures and whether it partly represents the 'G' in G×E effects. In all three domains, G×E effects were pervasive across country and gender, with small-to-moderate effects. Age-cohort trends were generally stable for BMI and depressive symptoms; however, they were variable-with both increasing and decreasing age-cohort trends-for different cognitive measures. Results also suggested that APOE may represent a 'variability gene' for depressive symptoms and spatial reasoning, but not for BMI or other cognitive measures. Hence, additional genes are salient beyond APOE.
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Affiliation(s)
- Chandra A Reynolds
- Department of Psychology, University of California Riverside, 900 University Ave., Riverside, CA, 92521, USA.
| | - Margaret Gatz
- Department of Psychology, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177, Stockholm, Sweden
| | - Kaare Christensen
- Epidemiology, Biostatistics and Bio-demography, Institute of Public Health, University of Southern Denmark, 5000, Odense C, Denmark
- Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
| | - Lene Christiansen
- Epidemiology, Biostatistics and Bio-demography, Institute of Public Health, University of Southern Denmark, 5000, Odense C, Denmark
| | - Anna K Dahl Aslan
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177, Stockholm, Sweden
- Institute of Gerontology, School of Health and Welfare, Jönköping University, Jönköping, Sweden
| | - Jaakko Kaprio
- Department of Public Health & Institute for Molecular Medicine FIMM, University of Helsinki, 00014, Helsinki, Finland
| | - Tellervo Korhonen
- Department of Public Health, University of Helsinki, 00014, Helsinki, Finland
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70211, Kuopio, Finland
| | - William S Kremen
- Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA
| | - Robert Krueger
- Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Matt McGue
- Epidemiology, Biostatistics and Bio-demography, Institute of Public Health, University of Southern Denmark, 5000, Odense C, Denmark
- Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Jenae M Neiderhiser
- Department of Psychology, The Pennsylvania State University, University Park, PA, USA
| | - Nancy L Pedersen
- Department of Psychology, University of Southern California, Los Angeles, CA, 90089, USA
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177, Stockholm, Sweden
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Petersen I, Pedersen NL, Rantanen T, Kremen WS, Johnson W, Panizzon MS, Christiansen L, Franz CE, McGue M, Christensen K, Hamdi NR, Krueger RF, Reynolds C. G×E Interaction Influences Trajectories of Hand Grip Strength. Behav Genet 2015; 46:20-30. [PMID: 26318288 DOI: 10.1007/s10519-015-9736-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 08/11/2015] [Indexed: 12/20/2022]
Abstract
Age-related decline in grip strength predicts later life disability, frailty, lower well-being and cognitive change. While grip strength is heritable, genetic influence on change in grip strength has been relatively ignored, with non-shared environmental influence identified as the primary contributor in a single longitudinal study. The extent to which gene-environment interplay, particularly gene-environment interactions, contributes to grip trajectories has yet to be examined. We considered longitudinal grip strength measurements in seven twin studies of aging in the Interplay of Genes and Environment across Multiple Studies consortium. Growth curve parameters were estimated for same-sex pairs, aged 34-99 (N = 10,681). Fisher's test for mixture distribution of within-monozygotic twin-pair differences (N = 1724) was performed on growth curve parameters. We observed significant gene-environment interaction on grip strength trajectories. Finally, we compared the variability of within-pair differences of growth curve parameters by APOE haplotypes. Though not statistically significant, the results suggested that APOE ɛ2ɛ2/ɛ2ɛ3 haplotypes might buffer environmental influences on grip strength trajectories.
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Affiliation(s)
- Inge Petersen
- The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
| | - Nancy L Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Taina Rantanen
- Gerontology Research Center and Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - William S Kremen
- Department of Psychiatry and Center for Behavioral Genomics, University of California, San Diego, La Jolla, CA, USA
- Center of Excellence for Stress and Mental Health, VA San Diego Healthcare Center, La Jolla, CA, USA
| | - Wendy Johnson
- Department of Psychology and Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - Matthew S Panizzon
- Department of Psychiatry and Center for Behavioral Genomics, University of California, San Diego, La Jolla, CA, USA
| | - Lene Christiansen
- The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark
| | - Carol E Franz
- Department of Psychiatry and Center for Behavioral Genomics, University of California, San Diego, La Jolla, CA, USA
| | - Matt McGue
- The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark
- Department of Psychology, University of Minnesota, Minneapolis, MN, USA
| | - Kaare Christensen
- The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
| | - Nayla R Hamdi
- Department of Psychology, University of Minnesota, Minneapolis, MN, USA
| | - Robert F Krueger
- Department of Psychology, University of Minnesota, Minneapolis, MN, USA
| | - Chandra Reynolds
- Department of Psychology, University of California - Riverside, Riverside, CA, USA
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McArdle JJ, Prescott CA. Contemporary Modeling of Gene × Environment Effects in Randomized Multivariate Longitudinal Studies. PERSPECTIVES ON PSYCHOLOGICAL SCIENCE 2015; 5:606-21. [PMID: 22472970 DOI: 10.1177/1745691610383510] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
There is a great deal of interest in the analysis of Genotype × Environment interactions (G×E). There are some limitations in the typical models for the analysis of G×E, including well-known statistical problems in identifying interactions and unobserved heterogeneity of persons across groups. The impact of a treatment may depend on the level of an unobserved variable, and this variation may dampen the estimated impact of treatment. Some researchers have noted that genetic variation may sometimes account for unobserved, and hence unaccounted for, heterogeneity. The statistical power associated with the G×E design has been studied in many different ways, and most results show that the small effects expected require relatively large or nonrepresentative samples (i.e., extreme groups). In this article, we describe some alternative approaches, such as randomized designs with multiple measures, multiple groups, multiple occasions, and analyses, to identify latent (unobserved) classes of people. These approaches are illustrated with data from the Aging, Demographics, and Memory Study (part of the Health and Retirement Study) examining the relations among episodic memory (based on word recall), APOE4 genotype, and educational attainment (as a proxy for an environmental exposure). Randomized clinical trials (RCTs) and randomized field trials (RFTs) have multiple strengths in the estimation of causal influences, and we discuss how measured genotypes can be incorporated into these designs. Use of these contemporary modeling techniques often requires different kinds of data be collected and encourages the formation of parsimonious models with fewer overall parameters, allowing specific G×E hypotheses to be investigated with a reasonable statistical foundation.
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Affiliation(s)
- John J McArdle
- Department of Psychology, University of Southern California, Los Angeles, CA
| | - Carol A Prescott
- Department of Psychology, University of Southern California, Los Angeles, CA
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7
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Reynolds CA, Finkel D. A meta-analysis of heritability of cognitive aging: minding the "missing heritability" gap. Neuropsychol Rev 2015; 25:97-112. [PMID: 25732892 DOI: 10.1007/s11065-015-9280-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 01/26/2015] [Indexed: 12/19/2022]
Abstract
The etiologies underlying variation in adult cognitive performance and cognitive aging have enjoyed much attention in the literature, but much of that attention has focused on broad factors, principally general cognitive ability. The current review provides meta-analyses of age trends in heritability of specific cognitive abilities and considers the profile of genetic and environmental factors contributing to cognitive aging to address the 'missing heritability' issue. Our findings, based upon evaluating 27 reports in the literature, indicate that verbal ability demonstrated declining heritability, after about age 60, as did spatial ability and perceptual speed more modestly. Trends for general memory, working memory, and spatial ability generally indicated stability, or small increases in heritability in mid-life. Equivocal results were found for executive function. A second meta-analysis then considered the gap between twin-based versus SNP-based heritability derived from population-based GWAS studies. Specifically, we considered twin correlation ratios to agnostically re-evaluate biometrical models across age and by cognitive domain. Results modestly suggest that nonadditive genetic variance may become increasingly important with age, especially for verbal ability. If so, this would support arguments that lower SNP-based heritability estimates result in part from uncaptured non-additive influences (e.g., dominance, gene-gene interactions), and possibly gene-environment (GE) correlations. Moreover, consistent with longitudinal twin studies of aging, as rearing environment becomes a distal factor, increasing genetic variance may result in part from nonadditive genetic influences or possible GE correlations. Sensitivity to life course dynamics is crucial to understanding etiological contributions to adult cognitive performance and cognitive aging.
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Affiliation(s)
- Chandra A Reynolds
- Department of Psychology, University of California Riverside, Riverside, CA, 92521, USA,
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McFall GP, Wiebe SA, Vergote D, Westaway D, Jhamandas J, Bäckman L, Dixon RA. ApoE and pulse pressure interactively influence level and change in the aging of episodic memory: Protective effects among ε2 carriers. Neuropsychology 2014; 29:388-401. [PMID: 25436424 DOI: 10.1037/neu0000150] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE We tested independent and interactive effects of Apolipoprotein E (ApoE) and pulse pressure (PP) concurrently and longitudinally across 9 years (3 waves) of episodic (EM) and semantic memory (SM) data from the Victoria Longitudinal Study. METHOD We assembled a sample of older adults (n = 570, baseline M age = 71, age range = 53-95) and used latent growth modeling to test 4 research goals. RESULTS First, the best fitting memory model was 2 single latent variables for EM and SM, each exhibiting configural, metric, and partial scalar invariance. This model was analyzed as a parallel process model. Second, baseline level of PP predicted EM performance at centering age (75) and rate of 9-year EM change. Third, we observed no main effects of ApoE on EM or SM. Fourth, EM was affected by higher PP but differentially less so for carriers of the ApoE ε2 allele than the ε3 or ε4 alleles. CONCLUSIONS PP is confirmed as a risk factor for concurrent and changing cognitive health in aging, but the effects operate differently across risk and protective allelic distribution of the ApoE gene.
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Jonaitis E, La Rue A, Mueller KD, Koscik RL, Hermann B, Sager MA. Cognitive activities and cognitive performance in middle-aged adults at risk for Alzheimer's disease. Psychol Aging 2014; 28:1004-14. [PMID: 24364404 DOI: 10.1037/a0034838] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Cognitive activity is thought to provide some protection against dementia, but the mechanism and timing of these effects are unknown. Data for this study were drawn from the Wisconsin Registry for Alzheimer's Prevention (WRAP), an at-risk middle-aged sample (mean age = 54 years) enriched for parental family history of Alzheimer's disease (AD). We had two main aims: (a) to determine the relative contribution of three facets of cognitive activity-education, occupational complexity with data, and cognitive leisure activities-to WRAP participants' cognitive performance; and (b) to assess for interactions between genetic risk factors and cognitive activity in explaining cognitive performance. Results from mixed effects models indicate that some of the variance usually attributed to education may be more closely accounted for by cognitive activities later in life. Overall, our analyses suggest cautious optimism for cognitive activities, especially game playing, as a strategy for preserving cognitive strengths in midlife.
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Affiliation(s)
- Erin Jonaitis
- Wisconsin Alzheimer's Institute, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison
| | - Asenath La Rue
- Wisconsin Alzheimer's Institute, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison
| | - Kimberly D Mueller
- Wisconsin Alzheimer's Institute, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison
| | - Rebecca L Koscik
- Wisconsin Alzheimer's Institute, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison
| | - Bruce Hermann
- Wisconsin Alzheimer's Institute, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison
| | - Mark A Sager
- Wisconsin Alzheimer's Institute, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison
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Brown AA, Buil A, Viñuela A, Lappalainen T, Zheng HF, Richards JB, Small KS, Spector TD, Dermitzakis ET, Durbin R. Genetic interactions affecting human gene expression identified by variance association mapping. eLife 2014; 3:e01381. [PMID: 24771767 PMCID: PMC4017648 DOI: 10.7554/elife.01381] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 03/13/2014] [Indexed: 01/09/2023] Open
Abstract
Non-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ∼70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits.DOI: http://dx.doi.org/10.7554/eLife.01381.001.
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Affiliation(s)
- Andrew Anand Brown
- Human Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Alfonso Buil
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland Institute of Genetics and Genomics in Geneva, University of Geneva Medical School, Geneva, Switzerland Swiss Institute of Bioinformatics, Geneva, Switzerland
| | - Ana Viñuela
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Tuuli Lappalainen
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland Institute of Genetics and Genomics in Geneva, University of Geneva Medical School, Geneva, Switzerland Swiss Institute of Bioinformatics, Geneva, Switzerland
| | - Hou-Feng Zheng
- Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, Canada
| | - J Brent Richards
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, Canada
| | - Kerrin S Small
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Timothy D Spector
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Emmanouil T Dermitzakis
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland Institute of Genetics and Genomics in Geneva, University of Geneva Medical School, Geneva, Switzerland Swiss Institute of Bioinformatics, Geneva, Switzerland
| | - Richard Durbin
- Human Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom
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Robert Plomin, John C. DeFries, Valerie S. Knopik, Jenae M. Neiderhiser, Behavioral Genetics (6th Edition). Behav Genet 2013. [DOI: 10.1007/s10519-013-9598-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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12
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Schneider JS, Anderson DW, Sonnenahalli H, Vadigepalli R. Sex-based differences in gene expression in hippocampus following postnatal lead exposure. Toxicol Appl Pharmacol 2011; 256:179-90. [PMID: 21864555 DOI: 10.1016/j.taap.2011.08.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 08/03/2011] [Accepted: 08/05/2011] [Indexed: 11/18/2022]
Abstract
The influence of sex as an effect modifier of childhood lead poisoning has received little systematic attention. Considering the paucity of information available concerning the interactive effects of lead and sex on the brain, the current study examined the interactive effects of lead and sex on gene expression patterns in the hippocampus, a structure involved in learning and memory. Male or female rats were fed either 1500 ppm lead-containing chow or control chow for 30 days beginning at weaning.Blood lead levels were 26.7±2.1 μg/dl and 27.1±1.7 μg/dl for females and males, respectively. The expression of 175 unique genes was differentially regulated between control male and female rats. A total of 167 unique genes were differentially expressed in response to lead in either males or females. Lead exposure had a significant effect without a significant difference between male and female responses in 77 of these genes. In another set of 71 genes, there were significant differences in male vs. female response. A third set of 30 genes was differentially expressed in opposite directions in males vs. females, with the majority of genes expressed at a lower level in females than in males. Highly differentially expressed genes in males and females following lead exposure were associated with diverse biological pathways and functions. These results show that a brief exposure to lead produced significant changes in expression of a variety of genes in the hippocampus and that the response of the brain to a given lead exposure may vary depending on sex.
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Affiliation(s)
- J S Schneider
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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Vasilopoulos T, Kremen WS, Kim K, Panizzon MS, Stein PK, Xian H, Grant MD, Lyons MJ, Toomey R, Eaves LJ, Franz CE, Jacobson KC. Untreated hypertension decreases heritability of cognition in late middle age. Behav Genet 2011; 42:107-20. [PMID: 21688193 DOI: 10.1007/s10519-011-9479-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Accepted: 06/01/2011] [Indexed: 10/18/2022]
Abstract
Hypertension is a risk factor for cognitive decline, but the mechanisms underlying the effects of hypertension on cognition, particularly in midlife, are unclear. We examined whether hypertension modifies genetic influences on individual differences in cognition. Nine cognitive domains and general cognitive ability were assessed in a sample of 1,237 male twins aged 51-60 who were divided into three blood pressure groups: non-hypertensive; medicated hypertensive; and unmedicated hypertensive. Heritability was significantly lower among unmedicated hypertensives compared to medicated hypertensives and non-hypertensives for visual-spatial ability (p = 0.013) and episodic memory (p = 0.004). There were no heritability differences between non-hypertensives and medicated hypertensives. In addition, there were no significant differences in mean level cognition across the three blood pressure groups. These results suggest that in middle-aged men, untreated hypertension suppresses normal genetic influences on individual differences in certain domains of cognition prior to the emergence of hypertension-related effects on cognitive performance. These results further suggest that antihypertensive medication may protect against or reverse this effect.
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Affiliation(s)
- Terrie Vasilopoulos
- Department of Psychiatry & Behavioral Neuroscience, University of Chicago, 5841 S Maryland Ave, MC 3077, rm 603, Chicago, IL 60637, USA.
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Abstract
BACKGROUND Collecting physical measurements in population-based health surveys has increased in recent years, yet little is known about the characteristics of those who consent to these measurements. OBJECTIVE To examine the characteristics of persons who consent to physical measurements across several domains, including one's demographic background, health status, resistance behavior toward the survey interview, and interviewer characteristics. RESEARCH DESIGN, SUBJECTS, AND MEASURES We conducted a secondary data analysis of the 2006 Health and Retirement Study, a nationally-representative panel survey of older adults aged 51 and older. We performed multilevel logistic regressions on a sample of 7457 respondents who were eligible for physical measurements. The primary outcome measure was consent to all physical measurements. RESULTS Seventy-nine percent (unweighted) of eligible respondents consented to all physical measurements. In weighted multilevel logistic regressions controlling for respondent demographics, current health status, survey resistance indicators, and interviewer characteristics, the propensity to consent was significantly greater among Hispanic respondents matched with bilingual Hispanic interviewers, patients with diabetes, and those who visited a doctor in the past 2 years. The propensity to consent was significantly lower among younger respondents, those who have several Nagi functional limitations and infrequently participate in "mildly vigorous" activities, and those interviewed by black interviewers. Survey resistance indicators, such as number of contact attempts and interviewer observations of resistant behavior in prior wave iterations of the Health and Retirement Study were also negatively associated with physical measurement consent. The propensity to consent was unrelated to prior medical diagnoses, including high blood pressure, cancer (excluding skin), lung disease, heart abnormalities, stroke, and arthritis, and matching of interviewer and respondent on race and gender. CONCLUSIONS Physical measurement consent is not strongly associated with one's health status, though the findings are somewhat mixed. We recommend that physical measurement results be adjusted for characteristics associated with the likelihood of consent, particularly functional limitations, to reduce potential bias. Otherwise, health researchers should exercise caution when generalizing physical measurement results to the population at large, including persons with functional limitations that may affect their participation.
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Sabb FW, Burggren AC, Higier RG, Fox J, He J, Parker DS, Poldrack RA, Chu W, Cannon TD, Freimer NB, Bilder RM. Challenges in phenotype definition in the whole-genome era: multivariate models of memory and intelligence. Neuroscience 2009; 164:88-107. [PMID: 19450667 DOI: 10.1016/j.neuroscience.2009.05.013] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2008] [Revised: 04/01/2009] [Accepted: 05/06/2009] [Indexed: 12/22/2022]
Abstract
Refining phenotypes for the study of neuropsychiatric disorders is of paramount importance in neuroscience. Poor phenotype definition provides the greatest obstacle for making progress in disorders like schizophrenia, bipolar disorder, Attention Deficit/Hyperactivity Disorder (ADHD), and autism. Using freely available informatics tools developed by the Consortium for Neuropsychiatric Phenomics (CNP), we provide a framework for defining and refining latent constructs used in neuroscience research and then apply this strategy to review known genetic contributions to memory and intelligence in healthy individuals. This approach can help us begin to build multi-level phenotype models that express the interactions between constructs necessary to understand complex neuropsychiatric diseases. These results are available online through the http://www.phenowiki.org database. Further work needs to be done in order to provide consensus-building applications for the broadly defined constructs used in neuroscience research.
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Affiliation(s)
- F W Sabb
- Consortium for Neuropsychiatric Phenomics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
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16
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Deary IJ, Johnson W, Houlihan LM. Genetic foundations of human intelligence. Hum Genet 2009; 126:215-32. [DOI: 10.1007/s00439-009-0655-4] [Citation(s) in RCA: 259] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2009] [Accepted: 03/08/2009] [Indexed: 02/07/2023]
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Lindenberger U, Nagel IE, Chicherio C, Li SC, Heekeren HR, Bäckman L. Age-related decline in brain resources modulates genetic effects on cognitive functioning. Front Neurosci 2008; 2:234-44. [PMID: 19225597 PMCID: PMC2622748 DOI: 10.3389/neuro.01.039.2008] [Citation(s) in RCA: 180] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2008] [Accepted: 11/11/2008] [Indexed: 01/17/2023] Open
Abstract
Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words)
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Taylor WD, Züchner S, McQuoid DR, Steffens DC, Blazer DG, Krishnan KRR. Social support in older individuals: the role of the BDNF Val66Met polymorphism. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:1205-12. [PMID: 18384075 PMCID: PMC2575229 DOI: 10.1002/ajmg.b.30754] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Although often viewed as a purely environmental construct, perception of social support may be influenced by genetic factors. This study examined the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and social support measures in older subjects. The sample consisted of 243 depressed and 115 nondepressed older subjects, age 60 years or older; 233 were Val66 allele homozygotes, while 125 were Met66 allele carriers. All subjects completed clinical assessments, including a self-report questionnaire assessing four social support domains, and provided blood for genotyping. Statistical models examined the relationship between scale scores of social support and BDNF Val66Met genotype, while controlling for presence or absence of major depressive disorder and other demographic factors significantly associated with social support. As social support measures were not normally distributed, log-transformed scores were examined. After controlling for diagnosis and education level, the Met66 allele was associated with lower levels of subjective social support (F(1,357) = 5.33, P = 0.0216) and a trend for fewer social interactions (F(1,357) = 3.66, P = 0.0567). To our knowledge, this is the first report associating a measure of social support with a genetic polymorphism. This supports previous work that genetic factors may influence social support perception. Further work is needed to determine the generalizability of this finding to the broader population, as well as its significance for clinical outcomes.
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Affiliation(s)
- Warren D. Taylor
- Department of Psychiatry, Duke University Medical Center, Durham, NC
| | - Stephan Züchner
- The Center for Human Genetics, Duke University Medical Center, Durham, NC, Department of Psychiatry, Duke University Medical Center, Durham, NC, The Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
| | | | - David C. Steffens
- Department of Psychiatry, Duke University Medical Center, Durham, NC
| | - Dan G. Blazer
- Department of Psychiatry, Duke University Medical Center, Durham, NC
| | - K. Ranga R. Krishnan
- Department of Psychiatry, Duke University Medical Center, Durham, NC, The Duke-NUS Graduate Medical School Singapore
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Dickerson F, Stallings C, Sullens A, Origoni A, Leister F, Krivogorsky B, Yolken R. Association between cognitive functioning, exposure to Herpes Simplex Virus type 1, and the COMT Val158Met genetic polymorphism in adults without a psychiatric disorder. Brain Behav Immun 2008; 22:1103-1107. [PMID: 18571372 DOI: 10.1016/j.bbi.2008.04.156] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2008] [Revised: 04/03/2008] [Accepted: 04/26/2008] [Indexed: 11/27/2022] Open
Abstract
Previous studies have documented that serologic evidence of infection with the neurotropic human herpesvirus Herpes Simplex Virus type 1 (HSV-1) is associated with increased levels of cognitive dysfunction in individuals with schizophrenia or bipolar disorder. The catechol-o-methyl transferase (COMT) Val158Met polymorphism has also been associated with cognitive dysfunction in individuals with psychiatric disorders as well as in some control populations. We examined whether these factors are independently associated with cognitive functioning in adults without a history of a psychiatric disorder. A total of 240 individuals were evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Wisconsin Card Sorting Test (WCST). We measured IgG antibodies to HSV-1 by enzyme immunoassay and employed real time PCR to measure COMT Val158Met genotypes. Serological evidence of HSV-1 was significantly associated with a lower RBANS total score independent of demographic factors and the COMT Val158Met genotype. The strongest association between cognitive functioning and serological evidence of HSV-1 infection was with the domain of delayed memory. Serological evidence of HSV-1 infection was associated with an 18-fold increased odds of having a severe impairment in this domain. The Val/Val genotype of the COMT Val158Met polymorphism was also significantly associated with the RBANS total score and with a moderate decrease in the domain of attention. Infections with HSV-1 and the COMT Val158Val genotype are risk factors for cognitive deficits in non-elderly persons without a psychiatric disorder.
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Affiliation(s)
- Faith Dickerson
- Stanley Research Program, Sheppard Pratt, Baltimore, MD, USA
| | | | - Anne Sullens
- Stanley Research Program, Sheppard Pratt, Baltimore, MD, USA
| | - Andrea Origoni
- Stanley Research Program, Sheppard Pratt, Baltimore, MD, USA
| | - Flora Leister
- Stanley Neurovirology Laboratory, Johns Hopkins School of Medicine, 600 N Wolfe Street, Baltimore, MD 21207, USA
| | - Bogdana Krivogorsky
- Stanley Neurovirology Laboratory, Johns Hopkins School of Medicine, 600 N Wolfe Street, Baltimore, MD 21207, USA
| | - Robert Yolken
- Stanley Neurovirology Laboratory, Johns Hopkins School of Medicine, 600 N Wolfe Street, Baltimore, MD 21207, USA.
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