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

Nat Commun. 2020;11(1):2301. Published 2020 May 8. doi:10.1038/s41467-020-16022-0

Authors/Editors: Shen X, Howard DM, Adams MJ, Hill WD, Clarke TK, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium [i.a. Müller-Myhsok B ], Deary IJ, Whalley HC, McIntosh AM.
Publication Date: 2020

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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.

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