Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

Aleix Arnau-Soler,Caroline Hayward,Andrew M Mcintosh,Keith Milburn,Mark J Adams,Donald J Macintyre,Generation Scotland ,Toni-Kim Clarke,Pippa A Thomson,Erin Macdonald-Dunlop,Major Depressive Disorder Working Group Of The Psychiatric Genomics Consortium ,Lauren Navrady

doi:10.1038/s41398-018-0360-y

Abstract

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10−6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10−9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10−8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10−8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10−6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10−3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

Highlights

Mental illness results from the interplay between genetic susceptibility and environmental risk factors[1,2]
Depressive symptom scores and stressful life events (SLE) measures were positively correlated in both UK Biobank (UKB) (r2 = 0.22, p < 2.2 × 10–16) and Generation Scotland (GS) (TSLE-r2 = 0.21, p = 1.69 × 10−52; DSLE-r2 = 0.21, p = 8.59 × 10−51; ISLE-r2 = 0.17, p = 2.33 × 10−33)
Single nucleotide polymorphisms (SNPs)-heritability (h2SNP) In UKB, a significant h2SNP of Patient Health Questionnaire (PHQ) was identified (h2SNP = 0.090; p < 0.001; N = 99,057). This estimate remained significant after adjusting by TSLEUKB effect (h2SNP = 0.079; p < 0.001), suggesting a genetic contribution unique to depressive symptoms

Summary

Introduction

Mental illness results from the interplay between genetic susceptibility and environmental risk factors[1,2]. Previous studies have shown that the effects of environmental factors on traits may be partially heritable[3] and moderated by genetics[4,5]. Major depressive disorder (MDD) is the most common psychiatric disorder with a lifetime prevalence of approximately 14% globally[6] and with a heritability of approximately 37%7. There is strong evidence for the role of stressful life events (SLEs) as risk factor and trigger for. Genetic control of sensitivity to stress may vary between individuals, resulting in individual differences in the depressogenic effects of SLE, i.e., genotype-byenvironment interaction (GxE)[4,13,14,15,16]. Significant evidence of GxE has been reported for common respiratory diseases and some forms of cancer[17,18,19,20,21,22], and GxE studies have identified genetic risk variants not found by genome-wide association studies (GWAS)[23,24,25,26,27]

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