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

Xueyi Shen, David M Howard, Mark J Adams, W David Hill, Toni-Kim Clarke, 23andMe Research Team, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Ian J Deary, Heather C Whalley and Andrew M McIntosh

Aug 28, 2019

Received Date: 23rd August 19

Depression is the leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Depression is known to be heritable with a polygenic architecture, and results from genome-wide association studies are generating summary statistics with increasing polygenic signal that can be used to estimate genetic risk scores for prediction in independent samples. This provides a timely opportunity to identify traits that are associated with polygenic risk of depression in the large and consistently phenotyped UK Biobank sample. Using the Psychiatric Genomics Consortium (PGC), 23andMe and non-imaging UK Biobank datasets as reference samples, we estimated polygenic risk scores for depression (depression-PRS) in a discovery sample of 10,674 people and a replication sample of 11,214 people from the UK Biobank Imaging Study, testing for associations with 209 behavioural and 343 neuroimaging phenotypes. In the discovery sample, 100 traits were significantly associated with depression-PRS after multiple testing correction. Among these, all traits were in the same direction, and 77 were significant in the replication analysis. For imaging traits that replicated across samples, higher depression-PRS was associated with lower global white matter microstructure, association-fibre and thalamic-radiation microstructural integrity (absolute β: 0.023 to 0.043, pFDR: 0.050 to 6.95×10-5). Mendelian Randomisation analysis showed a causal effect of liability to depression on these structural brain measures (β: 0.125 to 0.868, pFDR<0.043). Replicated behavioural traits that positively associated with depression-PRS included sleep problems, smoking status, measures of pain and stressful life experiences, and those negatively associated with depression-PRS included subjective ratings of physical health (absolute β: 0.014 to 0.180, pFDR: 0.049 to 1.28×10-14). Effect of depression PRS on mental health in the presence of reported childhood trauma and those living in more socially deprived areas showed increased variance explained by 1.67 – 3.57 times (pFDR for their interaction with depression-PRS: 0.040 to 0.010). Overall, the present study revealed replicable associations between depression-PRS and white matter microstructure that appeared to be a causal consequence of depression. Analyses provided further evidence that greater effects of polygenic risk of depression are found in individuals exposed to risk-conferring environments.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature