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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,  p  FDR  < 0.043). Several behavioural traits are also associated with depression-PRS ( β : 0.014 to 0.180,  p  FDR : 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.

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