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

Xueyi Shen, Andrew M McIntosh, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, A. Abdellaoui, Eske M. Derks, C.V. Dolan, Jouke Jan Hottenga, Rick Jansen, Hamdi Mbarek, C.M. Middeldorp, Michel Nivard, Wouter J Peyrot, Danielle Posthuma, Gonneke Willemsen, D.I. Boomsma, Eco J.C. de Geus, Brenda W J H Penninx

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Article number2301
Pages (from-to)2301
JournalNature Communications
Issue number1
Publication statusPublished - 8 May 2020


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. Participation of the UK Biobank subjects is gratefully appreciated. We also thank UK Biobank team for collecting and preparing data for analyses. 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). We thank the research participants and employees of 23andMe for supporting this study. 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.

FundersFunder number
Sackler Trust
US National Institute of Mental Health5 U01MH109528-03
National Institute of Mental HealthU01MH109528
Brain and Behavior Research Foundation27404
National Alliance for Research on Schizophrenia and Depression
Wellcome Trust104036/Z/14/Z, MC_PC_17209
Royal College of Physicians of Edinburgh
Medical Research Council
Biotechnology and Biological Sciences Research Council
Age UK
University of Edinburgh213674/Z/18/Z
China Scholarship Council201506040037
Wellcome Trust Centre for Mitochondrial Research

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