Genetic sensitivity to environmental stress predicts major depressive disorder in UK Biobank and Generation Scotland: Scottish Family Health Study

1. Medical Genetics Section, University of Edinburgh, Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Edinburgh, UK ; (Aleix Arnau-Soler, Stewart W. Morris & Pippa A. Thomson)
2. Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK ; (Mark J. Adams)
3. A collaboration between the University Medical School and NHS in Aberdeen, Dundee, Edinburgh and Glasgow, Scotland, UK ; (Generation Scotland)
4. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK ; (Caroline Hayward)
5. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK ; (Pippa A. Thomson)

Major depressive disorder (MDD) is a complex disorder involving both genetic and environmental factors such as adverse life events. A genetic contribution has been suggested for the effects of adverse life events on risk of MDD. We sought to confirm this and identify genes involved in stress-sensitivity. Neuroticism is an endophenotype of MDD and has been used previously as a measure of stress-sensitivity. We identified loci at which the effect of the allele on neuroticism score was dependent on MDD status by performing an interaction genome-wide association study (GWAS). We defined the difference in allelic effect between cases and controls as stress-sensitivity and used polygenic risk scores weighted by stress-sensitivity to predict MDD. The meta-analysis of interaction GWAS in both Generation Scotland: Scottish Family Health Study (GS:SFHS) and UK Biobank (UKB) identified eight regions of suggestive association (P<1x10-5) with stress-sensitivity. The two loci with the strongest association overlap PTP4A1-PHF3-EYS and ZNF366 regions previously associated with alcohol consumption. Polygenic risk scores derived from the stress-sensitivity GWAS significantly improve the prediction of MDD risk by up to 64.3% in GS:SFHS (P=1.6x10-3) and 17.1% in UKB (P=0.044). Thus, this study confirms a significant genetic effect of stress-sensitivity on MDD risk in at least a subset of individuals and identifies a potential genetic link with alcohol intake. Stress-sensitivity could be used to identify a subtype of MDD patients, even in the absence of information on adverse life events, and may permit targeted provision of prevention strategies.

* entered into the PhD student poster competition