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*


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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.

TidsskriftBiological Psychiatry Global Open Science
Udgave nummer4
Sider (fra-til)400-410
StatusUdgivet - okt. 2022

Bibliografisk note

Funding Information:
The iPSYCH project is funded by the Lundbeck Foundation (Grant Nos. R102-A9118, R155-2014-1724, and R248-2017-2003) and the universities and university hospitals of Aarhus and Copenhagen. KLM is funded by a postodoc fellowship from the Lundbeck Foundation (Grant No. R303-2018-3551). Genotyping of the iPSYCH2012 samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (Grant No. SFARI 311789), and the National Institute of Mental Health (Grant No. 5U01MH094432-02). The Danish National Biobank resource is supported by the Novo Nordisk Foundation. The UK Biobank (Project ID 16577) represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. High-performance computing facilities at the NIHR Biomedical Research Centre were funded with capital equipment grants from the Guy's and St Thomas’ NHS Foundation Trust Charity (Grant No. TR130505) and Maudsley Charity (Grant No. 980). The authors gratefully acknowledge the Broad Institute for genotyping. Initial genetic analyses were performed on the GenomeDK high-performance computing facility supported by the Centre for Genomics and Personalized Medicine and Center for Integrative Sequencing, Aarhus University. A previous version of this article was published as a preprint on medRxiv: TW has served as scientific advisor to H. Lundbeck A/S. GB has received consultancy and speaker fees from Eli Lilly, Otsuka, and Illumina. All other authors report no biomedical financial interests or potential conflicts of interest.


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