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Nat Commun . 2020 May 8;

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

Liron Malki, Ofer Sarig, Nicole Cesarato, Janan Mohamad, Talia Canter, Sari Assaf, Mor Pavlovsky, Dan Vodo, Yossi Anis, Ofer Bihari, Kiril Malovitski, Andrea Gat, Holger Thiele, Bethany E Perez White, Liat Samuelov, Arti Nanda, Amy S Paller, Regina C Betz, Eli Sprecher, Xueyi Shen, David M Howard, Mark J Adams, W David Hill, Toni-Kim Clarke, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Ian J Deary, Heather C Whalley, Andrew M McIntosh

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.

PMID: 32385265