LAUSR

Background Risk for depression is attributable to both genes and life stress such as childhood maltreatment or death of a close relative. Candidate gene studies have indicated that life stress interacts with single genetic variants to influence depression risk. Further, the genetic architecture of depression is highly polygenic, with genetic risk for depression primarily determined by small effects of multiple genetic variants which might also interact collectively with environmental factors. The aim of this study is to investigate gene-environment interaction in depression using three separate measures of genetic risk: a) candidate genetic variants, b) polygenic risk scores and c) a Genome-Wide Interaction Study (GWIS) based on 500,000 SNPs distributed across the genome. Methods In the iPSYCH case-cohort study we identified 18,431 cases and 20,163 random subcohort members for whom GWAS analyses were available. All cases were diagnosed with depression at a Danish psychiatric hospital. We used nationwide Danish registers to obtain information on the life stressors: childhood abuse, family disruption, disability pension in a parent, severe somatic disease of the index person and severe somatic disease and death of first-degree relatives. Information on life stress was operationalized as a cumulative time-dependent variable. Our analyses include 180 specific candidate genetic variants previously reported to take part in gene-environment interaction in depression or identified as directly associated with depression in GWASs. Further, we evaluate if a polygenetic risk score interacts with life stress to predict depression. Finally, we apply an agnostic approach investigating if any of 500,000 SNPs selected from across the genome interact with early life stress on risk for depression. We applied extended Cox models with Prentice weighting of cases for analyses. Sex, birth cohort and principal components were included as covariates. Results At the time of abstract submission we have conducted preliminary analyses. Final analyses will be presented at the WCPG, 2017. Discussion To our best knowledge, this study will be the largest original investigation to date on gene-environment interaction in depression. We expect that the results will provide new insights to the understanding of the combined effects of nature and nurture on risk for depression.