Genome-wide by environment interaction study of stressful life events and hospital-treated depression in the iPSYCH2012 sample

Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. We conducted a genome-wide by environment interaction study (GWEIS) in 18,532 patients with depression from hospital-based settings and 20,184 population controls. All individuals were drawn from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Information on stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability, and child maltreatment was identified from the registers and operationalized as a time-varying count variable. Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. Our replication sample included 22,880 depression cases and 50,378 controls from the UK Biobank. The GWEIS in the iPSYCH2012 sample yielded three novel, genome-wide–significant ( p < 5 × 10 −8 ) loci located in the ABCC1 gene (rs56076205, p = 3.7 × 10 −10 ), the AKAP6 gene (rs3784187, p = 1.2 × 10 −8 ), and near the MFSD1 gene (rs340315, p = 4.5 × 10 −8 ). No hits replicated in the UK Biobank (rs56076205: p = .87; rs3784187: p = .93; rs340315: p = .71). In this large, population-based GWEIS, we did not find any replicable hits for interaction. Future gene-by-stress research in depression should focus on establishing even larger collaborative GWEISs to attain sufficient power.