Genome-wide by Environment Interaction Study of Stressful Life Events and Hospital-Treated Depression in the iPSYCH2012 Sample

Nis P. Suppli, Klaus K. Andersen, Esben Agerbo, Veera M. Rajagopal, Vivek Appadurai, Jonathan R.I. Coleman, Gerome Breen, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Carsten B. Pedersen, Marianne G. Pedersen, Wesley K. Thompson, Trine Munk-Olsen, Michael E. Benros, Thomas D. Als, Jakob Grove, Thomas Werge, Anders D. Børglum, David M. Hougaard, Ole MorsMerete Nordentoft, Preben B. Mortensen, Katherine L. Musliner*

*Corresponding author for this work

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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.

Original languageEnglish
JournalBiological Psychiatry Global Open Science
Issue number4
Pages (from-to)400-410
Publication statusPublished - Oct 2022

Bibliographical note

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© 2021 The Authors


  • Case-cohort studies
  • Depression
  • Genetics
  • GXE
  • Register-based research
  • Stress


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