Genome-wide by Environment Interaction Study of Stressful Life Events and Hospital-Treated Depression in the iPSYCH2012 Sample
Nis P. Suppli, Klaus Kaae Andersen, Esben Agerbo, Veera M. Rajagopal, Vivek Appadurai, Jonathan R. I. Coleman, Gerome Breen, Jonas Bybjerg‐Grauholm, Marie Bækvad‐Hansen, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Wesley K. Thompson, Trine Munk‐Olsen, Michael E. Benros, Thomas D. Als, Jakob Grove, Thomas Werge, Anders D. Børglum, David M. Hougaard, Ole Mors, Merete Nordentoft, Preben Bo Mortensen, Katherine L. Musliner
Abstract
Background 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. Methods 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 . Results 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). Conclusions 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.