Genome-Wide Association Study (Gwas) and Genome-Wide by Environment Interaction Study (Gweis) of Depressive Symptoms in African American and Hispanic/Latina Women

Abstract

Background Genome-wide association studies (GWAS) have been unable to identify variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (G×E) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide environment interaction study (GWEIS) of depressive symptoms. Methods Using data from the SHARe cohort of the Women’s Health Initiative, comprising African Americans (n=7179) and Hispanics/Latinas (n=3138), we examined genetic main effects and G×E 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. Results No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20kb 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 27kb from CD38, p=2.44×10−7) and rs4542757 (intronic to DCC, p=7.31×10−7). In the GWEIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; p=4.10×10−10; located 14kb 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 depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. Conclusions Our results underscore the need for larger samples, more GWEIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.

Genetic and environmental determinants of stressful life events and their overlap with depression and neuroticism

“…Using LD score regression, we found that the genetic overlap between dependent life events and MDD (0.60) was nominally higher than for independent life events (0.20). This is in line with the findings by Dunn et al who found a strong genetic correlation between MDD and SLEs in women (r G =0.95) 23 . The genetic overlap between SLEs and MDD calls for a different interpretation of the effect of SLEs on MDD.…”

“…When personal SLEs were analysed modelling both genetic and environmental components, the SNP heritability estimate was significant and accounted for 8% of the variance in SLEs. This is the same as the estimate derived from the population-based study of African American women that found the SNP heritability of SLEs to be 8% 23 . However, another study found SNP effects account for roughly a third of variance in SLEs 22 .…”

“…One study estimated the SNP heritability of SLEs to be 29% (p=0.03, S.E.=0.16) in a sample of 2578 unrelated individuals enriched for MDD cases 22 . However, another study of 7179 African American women found the SNP heritability of SLEs to be only 8% (p=0.02, S.E.=0.04) 23 . A significant genetic correlation between SLEs and MDD in African American women was observed by Dunn et al (r=0.95,p=0.01) using bivariate GCTA-GREML, suggesting that genetic variants that influence MDD risk are also relevant for SLEs 23 .…”

“…However, another study of 7179 African American women found the SNP heritability of SLEs to be only 8% (p=0.02, S.E.=0.04) 23 . A significant genetic correlation between SLEs and MDD in African American women was observed by Dunn et al (r=0.95,p=0.01) using bivariate GCTA-GREML, suggesting that genetic variants that influence MDD risk are also relevant for SLEs 23 . The difference in heritability estimates for SLEs may be the result of different genetic architectures and familial or environmental effects across the two samples.…”

Making Dopamine Connections in Adolescence

“…A second notable link between psychiatric disease and altered DCC epigenetics is an increase of about 50% in DCC gene expression in the prefrontal cortex of antidepressant-free patients with major depressive disorder who committed suicide [29], a finding later replicated [53]. In fact, there is now substantial correlational genetic evidence from human populations that variation in DCC expression is a risk factor for depression [29,53,79–82]. Although such evidence lacks a causative link, using a mouse model of depression we have recently shown that increased Dcc expression in the prefrontal cortex induces susceptibility to developing depression-like phenotypes [53].…”