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

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.

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

“…Moreover, using pathway analyses in two independent samples (n = 6455, n = 18,759), FDRcorrected associations between depression and a Netrin-1 signaling pathway were identified, comprising SNPs from multiple genes involved in Netrin-1 signaling, including DCC [66]. Additionally, gene-based tests found that depressive symptoms among participants in the UK Biobank (n = 99,057) were associated with six genes, including DCC [67]. Another UK Biobank (n = 122,935) gene-based analysis found associations between suicidality and five genes, including DCC [68].…”

GxEsum: a novel approach to estimate the phenotypic variance explained by genome-wide GxE interaction based on GWAS summary statistics for biobank-scale data

“…However, the analytical modelling used in GWAS and whole-genome approaches usually assumes that there is no genotype-environment interaction (GxE), which can be often violated against the true genetic architecture of complex traits. Indeed, interaction is fundamental in biology and there has been increasing interest in estimating GxE, using genome-wide SNPs [5][6][7] .…”

Genome‐wide interaction study of single‐nucleotide polymorphisms and alcohol consumption on blood pressure: The Ansan and Ansung study of the Korean Genome and Epidemiology Study (KoGES)

“…In the present study, there was the likelihood of systematic inflation on the significance of interaction. To correct heteroscedasticity on the analysis, methods that use the robust standard error ( SE ) were proposed (Voorman et al, 2011); there was some evidence when those methods were used (Almli et al, 2014; Arnau‐Soler et al, 2019). However, we could not correct the systematic inflation on our data set even when using the robust SE approach as well as adjusting the principle component for population stratification (data not shown).…”