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 Mors; Merete Nordentoft; Preben B Mortensen; Katherine L Musliner

doi:10.1016/j.bpsgos.2021.11.003

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

Biol Psychiatry Glob Open Sci. 2021 Nov 9;2(4):400-410. doi: 10.1016/j.bpsgos.2021.11.003. eCollection 2022 Oct.

Authors

Nis P Suppli^{1

2}, Klaus K Andersen³, Esben Agerbo^{1

4

5}, Veera M Rajagopal^{1

6

7

8}, Vivek Appadurai^{1

9}, Jonathan R I Coleman^{10

11}, Gerome Breen^{10

11}, Jonas Bybjerg-Grauholm^{1

12}, Marie Bækvad-Hansen^{1

12}, Carsten B Pedersen^{1

4

5}, Marianne G Pedersen^{1

4

5}, Wesley K Thompson^{1

13}, Trine Munk-Olsen^{1

4

14}, Michael E Benros^{1

2

15}, Thomas D Als^{1

6

7

8}, Jakob Grove^{1

6

7

16

8}, Thomas Werge^{1

9}, Anders D Børglum^{1

6

7

8}, David M Hougaard^{1

12}, Ole Mors^{1

17}, Merete Nordentoft^{1

2}, Preben B Mortensen^{1

4

5}, Katherine L Musliner^{1

4

18

19}

Affiliations

¹ Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
² Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
³ Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark.
⁴ National Centre for Register-based Research, Department of Economics, Aarhus University, Aarhus, Denmark.
⁵ Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷ Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
⁸ Center for Genomics and Personalized Medicine, Aarhus, Denmark.
⁹ Institute of Biological Psychiatry, Copenhagen Mental Health Services, Copenhagen, Denmark.
¹⁰ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
¹¹ National Institute for Health Research Biomedical Research Centre, South London and Maudsley NHS Trust, London, United Kingdom.
¹² Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark.
¹³ Division of Biostatistics, Herbert Wertheim School of Public Health, University of California San Diego, La Jolla, California.
¹⁴ Department of Clinical Medicine, University of Southern Denmark, Odense, Denmark.
¹⁵ Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
¹⁷ Psychosis Research Unit, Aarhus University Hospital-Psychiatry, Aarhus.
¹⁸ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
¹⁹ Department of Affective Disorders, Aarhus University Hospital-Psychiatry, Aarhus, Denmark.

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.

Keywords: Case-cohort studies; Depression; GXE; Genetics; Register-based research; Stress.