Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland.
Ontology highlight
ABSTRACT:
SUBMITTER: Arnau-Soler A
PROVIDER: S-EPMC6361928 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Genome-wide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder (MDD). Haplotype data provide an alternative method for detecting associations between variants in weak linkage disequilibrium with genotyped variants and a given trait of interest. A genome-wide haplotype association study for MDD was undertaken utilising a family-based population cohort, Generation Scotland: Scottish Family Health Study (n = 18,773), as a discovery cohort with UK Biobank used as a population-based replication cohort (n = 25,035). Fine mapping of haplotype boundaries was used to account for overlapping haplotypes potentially tagging the same causal variant. Within the discovery cohort, two haplotypes exceeded genome-wide significance (P < 5 × 10-8) for an association with MDD. One of these haplotypes was nominally significant in the replication cohort (P < 0.05) and was located in 6q21, a region which has been previously associated with bipolar disorder, a psychiatric disorder that is phenotypically and genetically correlated with MDD. Several haplotypes with P < 10-7 in the discovery cohort were located within gene coding regions associated with diseases that are comorbid with MDD. Using such haplotypes to highlight regions for sequencing may lead to the identification of the underlying causal variants.
| S-EPMC5802488 | biostudies-literature
Project description:Few replicable genetic associations for Major Depressive Disorder (MDD) have been identified. Recent studies of MDD have identified common risk variants by using a broader phenotype definition in very large samples, or by reducing phenotypic and ancestral heterogeneity. We sought to ascertain whether it is more informative to maximize the sample size using data from all available cases and controls, or to use a sex or recurrent stratified subset of affected individuals. To test this, we compared heritability estimates, genetic correlation with other traits, variance explained by MDD polygenic score, and variants identified by genome-wide meta-analysis for broad and narrow MDD classifications in two large British cohorts - Generation Scotland and UK Biobank. Genome-wide meta-analysis of MDD in males yielded one genome-wide significant locus on 3p22.3, with three genes in this region (CRTAP, GLB1, and TMPPE) demonstrating a significant association in gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD yielded equivalent heritability estimates, showed no detectable difference in association with polygenic scores, and were each genetically correlated with six health-correlated traits (neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder). Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, and the consistent pattern of results in other MDD classifications suggests that phenotypic stratification using recurrence or sex in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain.
| S-EPMC5802463 | biostudies-literature
Project description:PurposeThis study aimed to investigate the associations between maternal smoking (MS) and education score in adult offspring.MethodsTo better understand this link, we performed a two-stage genome-wide by environment interaction studies (GWEIS) of MS and offspring education score in UK Biobank cohort. Specifically, 276 996 subjects from England were enrolled in the discovery study, while 24 355 subjects from Scotland and 14 526 subjects from Wales were enrolled in the replication study. GWEIS were conducted by PLINK 2.0 with MS used as an environmental risk factor.ResultsSignificant GWEIS associations ( P < 0.0001) between MS and offspring education score in both the discovery cohort and two replicate cohorts (Scotland population and Wales population) were identified. GWEIS identified 2 independent significant single nucleotide polymorphism-MS interaction, with one variant located in the chromosomal 16 (rs72768988, Position: 22,768,798, P = 1.22 × 10 -8 , β = 6.7662) and the other one located in 2q32.3 region (2 : 196424612_GT_G, Position: 196 424 612, 3.60 × 10 -9 , β = -0.4721).ConclusionOur results suggested 2q32.3 region and HECW2 gene could negatively moderate the influence of MS on offspring's educational status.
| S-EPMC10325563 | biostudies-literature
Project description:Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.
| S-EPMC7305950 | biostudies-literature
Project description:BackgroundThe association between sexual and physical abuse and subsequent depression is well-established, but the associations with specific depressive symptoms and sex differences remain relatively understudied. We investigated the associations of sexual and physical abuse with depressive symptoms in men and women in a large population cohort.MethodsObservational study based on 151,396 UK Biobank participants. Exposures included self-reported experiences of childhood physical abuse and sexual abuse. Mid-life outcomes included current depressive symptoms score, individual depressive symptoms, and lifetime depression. We used logistic regression to test associations of childhood sexual/physical abuse with depressive outcomes.ResultsRecalled childhood sexual and physical abuse were both associated with current depressive symptoms score in adults. Results for individual symptoms-based analyses suggest that sexual and physical abuse are associated with all depressive symptoms, particularly suicidal behaviours. The associations between lifetime depression and sexual/physical abuse were not fully explained by current depressive symptoms score, indicating that these findings may not be fully attributable to recall bias. There was no indication of differential risk for specific depressive symptoms among men and women.ConclusionsSexual and physical abuse are robust risk factors for depression/depressive symptoms regardless of sex. Higher risk of suicidal behaviours associated with childhood sexual/physical abuse are of particular concern. Longitudinal research into sex-specific associations for individual depressive symptoms is required.
| S-EPMC8127207 | biostudies-literature
Project description:BackgroundGenome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms.MethodsUsing data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts.ResultsNo SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10(-8) ) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10(-7) ). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10(-7) ) and rs4542757 (intronic to DCC, P = 7.31 × 10(-7) ). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10(-10) ; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample.ConclusionsOur results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.
| S-EPMC4826276 | biostudies-literature
Project description:BackgroundCognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants.MethodsIn the present analysis, three cohort studies (n total = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions.ResultsNone of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator ( DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer's disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10 -7), was the butyrylcholinesterase ( BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer's disease and its role in cognitive ability merits further investigation.ConclusionsAlthough no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.
| S-EPMC5605947 | biostudies-literature
Project description:Although commuting provides an opportunity for incorporating physical activity into daily routines, little is known about the effect of active commuting upon depressive symptoms. This study aimed to determine whether changes in commute mode are associated with differences in the severity of depressive symptoms in working adults. Commuters were selected from the UK Biobank cohort if they completed ?2 assessment centre visits between 2006 and 2016. Modes of travel to work were self-reported at each visit. Participants were categorised as 'inactive' (car only) or 'active' commuters (any other mode(s), including walking, cycling and public transport). Transitions between categories were defined between pairs of visits. The severity of depressive symptoms was defined using the two-item Patient Health Questionnaire (PHQ-2). Scores were derived between zero and six. Higher values indicate more severe symptoms. Separate analyses were conducted in commuters who were asymptomatic (zero score) and symptomatic (non-zero score) at baseline. The analytical sample comprised 5474 participants aged 40-75 at baseline with a mean follow-up of 4.65?years. Asymptomatic commuters who transitioned from inactive to active commuting reported less severe symptoms at follow-up than those who remained inactive (? -0.10, 95% CI [-0.20, 0.00]; N?=?3145). A similar but non-significant relationship is evident among commuters with pre-existing symptoms (? -0.60, 95% CI [-1.27, 0.08]; N?=?1078). After adjusting for transition category, longer commutes at baseline were associated with worse depressive symptoms at follow-up among symptomatic participants. Shifting from exclusive car use towards more active commuting may help prevent and attenuate depressive symptoms in working adults.
| S-EPMC5999356 | biostudies-other
Project description:Genetic susceptibility and lifestyle affect the risk of dementia but there is little direct evidence for their associations with preclinical changes in brain structure. We investigated the association of genetic dementia risk and healthy lifestyle with brain morphometry, and whether effects from elevated genetic risk are modified by lifestyle changes. We used prospective data from up to 25,894 UK Biobank participants (median follow-up of 8.8 years), and defined healthy lifestyle according to American Heart Association criteria as BMI < 30, no smoking, healthy diet and regular physical activity). Higher genetic risk was associated with lower hippocampal volume (beta -0.16 cm3, 95% CI -0.22, -0.11) and total brain volume (-4.34 cm3, 95% CI -7.68, -1.01) in participants aged ≥60 years but not <60 years. Healthy lifestyle was associated with higher total brain, grey matter and hippocampal volumes, and lower volume of white matter hyperintensities, with no effect modification by age or genetic risk. In conclusion, adverse effects of high genetic risk on brain health were only found in older participants, while adhering to healthy lifestyle recommendations is beneficial regardless of age or genetic risk.
| S-EPMC9570683 | biostudies-literature
Project description:We aimed to explore the underlying genetic mechanisms of traumatic events during childhood affecting the risks of adult substance use in present study. Using UK Biobank cohort, linear regression model was first applied to assess the relationships between cigarette smoking and alcohol drinking in adults with traumatic events during childhood, including felt hated by family member (41,648-111,465), felt loved (46,394-124,481) and sexually molested (47,598-127,766). Using traumatic events as exposure variables, genome-wide by environment interaction study was then performed by PLINK 2.0 to identify cigarette smoking and alcohol drinking associated genes interacting with traumatic events during childhood. We found that the frequency of cigarette smoking was significantly associated with felt hated by family member (coefficient = 0.42, P < 1.0 × 10-9), felt loved (coefficient = -0.31, P < 1.0 × 10-9) and sexually molested (coefficient = 0.46, P < 1.0 × 10-9). We also observed weaker associations of alcohol drinking with felt hated by family member (coefficient = 0.08, P = 3.10 × 10-6) and felt loved (coefficient = -0.06, P = 3.15 × 10-7). GWEIS identified multiple candidate loci interacting with traumatic events, such as CTNNA3 (rs189142060, P = 4.23 × 10-8) between felt hated by family member and the frequency of cigarette smoking, GABRG3 (rs117020886, P = 2.77 × 10-8) between felt hated by family member and the frequency of alcohol drinking. Our results suggested the significant impact of traumatic events during childhood on the risk of cigarette smoking and alcohol drinking.
| S-EPMC8379203 | biostudies-literature