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 environment interaction study in 18,532 depression cases from hospital-based settings and 20,184 population-representative non-cases from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability and child maltreatment were identified from population-based registers and operationalized as a time-varying count variable (0-4+). Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. The analyses yielded three novel, genome-wide significant (P < 5 x 10-8) loci located in the ATP-binding cassette transporter C 1 (ABCC1) gene, in the A-kinase anchor protein 6 (AKAP6) gene, and near the Major facilitator superfamily domain 1 (MFSD1) gene, as well as 50 loci of suggestive significance. These top 3 hits did not replicate in a case-control sample of depression drawn from the UK Biobank. These results suggest that there may be individual genetic variants that confer risk for or protection against clinical depression only in the presence of stressful life events; however, replication in a sample with similar design and ascertainment methods is needed before any firm conclusions can be drawn. Future gene-by-stress research in depression should focus on establishing even larger collaborative genome-wide environment interaction studies to attain sufficient power.