A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

Shen, X., Howard, D. M., Adams, M. J., Hill, W. D., Clarke, T.-K., Major Depressive Disorder Working Group of the PGC, ., Deary, I. J., Whalley, H. C. and McIntosh, A. M. (2020) A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank. Nature Communications, 11, 2301. (doi: 10.1038/s41467-020-16022-0) (PMID:32385265) (PMCID:PMC7210889)

Abstract

Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, pFDR: 0.049 to 1.28 × 10−14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.

• Item Type: Articles
• Additional Information: The present study is supported by a Wellcome Trust Strategic Award “Stratifying Resilience and Depression Longitudinally” (STRADL) (Reference 104036/Z/14/Z) and MRC Mental Health Data Pathfinder Award (Reference MC_PC_17209). Data acquisition and analyses were conducted using the UK Biobank Resource under approved project #4844. Funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. The PGC has received major funding from the US National Institute of Mental Health (5 U01MH109528-03). X.S. receives support from China Scholarship Council (No. 201506040037). H.C.W. is supported by a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh and by an ESAT College Fellowship from the University of Edinburgh. D.M.H. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Reference 213674/Z/18/Z) and a 2018 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (Reference 27404). W.D.H. is supported by a grant from Age UK (Disconnected Mind Project). A.M.M. is supported by the Sackler Trust. I.J.D. is a participant in UK Biobank.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Daniel
• Authors: Shen, X., Howard, D. M., Adams, M. J., Hill, W. D., Clarke, T.-K., Major Depressive Disorder Working Group of the PGC, ., Deary, I. J., Whalley, H. C., and McIntosh, A. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © The Author(s) 2020
• First Published: First published in Nature Communications 11:2301
• Publisher Policy: Reproduced under a Creative Commons license