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  • 1
    In: Translational Psychiatry, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-01-10)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2158-3188
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2609311-X
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  • 2
    In: Translational Psychiatry, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-01-18)
    Abstract: Depression has well-established influences from genetic and environmental risk factors. This has led to the diathesis-stress theory, which assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. Recently, Colodro-Conde et al . empirically tested this theory, using the polygenic risk score for major depressive disorder (PRS, genes) and stressful life events (SLE, environment) effects on depressive symptoms, identifying significant GxE effects with an additive contribution to liability. We have tested the diathesis-stress theory on an independent sample of 4919 individuals. We identified nominally significant positive GxE effects in the full cohort ( R 2  = 0.08%, p  = 0.049) and in women ( R 2  = 0.19%, p  = 0.017), but not in men ( R 2  = 0.15%, p  = 0.07). GxE effects were nominally significant, but only in women, when SLE were split into those in which the respondent plays an active or passive role ( R 2  = 0.15%, p  = 0.038; R 2  = 0.16%, p  = 0.033, respectively). High PRS increased the risk of depression in participants reporting high numbers of SLE ( p  = 2.86 × 10 −4 ). However, in those participants who reported no recent SLE, a higher PRS appeared to increase the risk of depressive symptoms in men ( β  = 0.082, p  = 0.016) but had a protective effect in women ( β  = −0.061, p  = 0.037). This difference was nominally significant ( p   =  0.017). Our study reinforces the evidence of additional risk in the aetiology of depression due to GxE effects. However, larger sample sizes are required to robustly validate these findings.
    Type of Medium: Online Resource
    ISSN: 2158-3188
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2609311-X
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  • 3
    In: Translational Psychiatry, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-02-04)
    Abstract: Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank ( DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p   〈  2.77 × 10 −6 ). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4 ; p  = 4.95 × 10 −9 ; total SLE) and rs17070072 (intronic to ZCCHC2 ; p  = 1.46 × 10 −8 ; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p   〈  2.00 × 10 −8 ; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank ( p   〈  2.77 × 10 −6 ). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms ( p  = 0.01) or the PGC GWAS of major depressive disorder ( p  = 5.91 × 10 −3 ). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.
    Type of Medium: Online Resource
    ISSN: 2158-3188
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2609311-X
    Location Call Number Limitation Availability
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