SU40 - DISTINCT GENETIC VULNERABILITIES-BY-STRESSFUL LIFE EVENTS INTERACTIONS PROPOSE ADDITIONAL RISK FOR DEPRESSIVE SYMPTOMS

Abstract

Background Stressful Life Events (SLEs) and genetic risk factors both contribute to the aetiology of Major Depressive Disorder (MDD). Although SLEs are considered to be an environmental factor, studies suggest that they may act in part through interaction with the known genetic risk factors in MDD or more unexpectedly, through interaction with novel genetic factors specific to SLEs. Polygenic Risk Scores (PRS) reflect an individual's genetic vulnerability to develop depression. Such vulnerability to MDD has been commonly based on main additive effects, although a genetic contribution has been suggested for SLEs on risk of MDD. We used PRS for MDD and for a novel stress-sensitivity trait, derived from a Genome-Wide Interaction Study (GWEIS), to test these hypotheses. Methods We performed a GWEIS in UK Biobank (N=23,092; UKB), modeling the interaction between SNP allele and MDD status on neuroticism score (EPQ-N). The effect size of the interaction term was used to create a measure of genetic MDD-dependent stress-sensitivity (SS). The genetic vulnerability-stress model was tested using PRS weighted by MDD using Psychiatric GWAS Consortium MDD summary statistics (MDD-PRS), or PRS weighted by MDD-dependent stress-sensitivity effect (SS-PRS) in GS:SFHS STRADL (Stratifying Depression and Resilience Longitudinally; N=4,919). GS:SFHS STRADL has data on symptoms of depression assessed by General Health Questionnaire (GHQ-28) and past 6 month SLEs using the List of Threatening Experiences (LTE-Q). Results MDD-PRS, SS-PRS and main effects of SLEs significantly predicted symptoms of depression (MDD-PRS: P=5.48×10-9; SS-PRS: P=2.63×10-4; SLEs: P=1.01×10–58, using best predictor at full cohort). The MDD-PRS-by-SLEs interaction significantly contributed to the risk of MDD at population level (p-threshold=0.01, β=0.028, SE=0.014, R2=0.077%, P=4.91×10-2), although this was stronger in females (p-threshold=1×10-5, β=0.044, SE=0.018, R2=0.19%, P=1.84×10-2) and not significant in males (p-threshold=0.1, β=0.04, SE=0.022, R2=0.16%, P=6.37×10-2). The SS-PRS-by-SLEs interaction significantly contributed to the risk of MDD in males (p-threshold=0.01, β=0.078, SE=0.022, R2=0.6%, P=3.38×10-4) but not in females (p-threshold=0.05, β=-0.027, SE=0.018, R2=0.075%, P=0.14) or in the full cohort (p-threshold=1×10-5, β=0.025, SE=0.014, R2=0.063%, P=7.75×10-2), This SS-PRS-by-SLEs interaction in males explained almost as much as the variance explained by the main MDD-PRS effect at their best predictor (p-threshold=0.102, β=0.081, SE=0.022, R2=0.66%, P=2.09×10-4). Discussion Significant genetic vulnerability-SLEs interactions predict and additional MDD risk for individuals with high predisposition and high number of reported SLEs. However, the results suggest distinct interactions between genetic vulnerabilities and SLEs on the aetiology of depression in males versus females, although replication on a larger sample would be required.