Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Arnau-Soler, Aleix, Adams, Mark J., Generation Scotland, , Major Depressive Disorder Working Group, , Hayward, Caroline, and Thompson, Pippa A. (2018) Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder. PLoS ONE, 13 (12). e0209160.

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Abstract

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48×10 -7 ; Bonferroni-corrected significance threshold p < 2.79×10 -6 ). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.

Item ID: 58594
Item Type: Article (Research - C1)
ISSN: 1932-6203
Copyright Information: © 2018 Arnau-Soler et al. This is an open access article distributed underthe terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Additional Information:

Grant Sinnamon is part of the is part of the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. All collaborators are listed at the end of the article.

Funders: Scottish Government Health Directorates (SGHD), Scottish Funding Council (SFC), US National Institute of Mental Health (NIMH), US National Institute of Drug Abuse (NIDA), Wellcome Trust
Projects and Grants: SGHD CZD/16/6, SFC [HR03006], NIDA U01 MH109528, NIDA U01 MH095320
Date Deposited: 12 Jun 2019 02:17
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110311 Medical Genetics (excl Cancer Genetics) @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1117 Public Health and Health Services > 111714 Mental Health @ 50%
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