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; Andrew M. McIntosh; Ian J. Deary; Heather C. Whalley; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s41467-020-16022-0

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, Andrew M. McIntosh^*, Ian J. Deary, Heather C. Whalley, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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, 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.

Original language	English
Article number	2301
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16022-0
Publication status	Published - 1 Dec 2020

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10.1038/s41467-020-16022-0

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Shen, X., Howard, D. M., Adams, M. J., Hill, W. D., Clarke, T. K., McIntosh, A. M., Deary, I. J., Whalley, H. C., & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2020). A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank. Nature Communications, 11(1), [2301]. https://doi.org/10.1038/s41467-020-16022-0

Shen, Xueyi ; Howard, David M. ; Adams, Mark J. ; Hill, W. David ; Clarke, Toni Kim ; McIntosh, Andrew M. ; Deary, Ian J. ; Whalley, Heather C. ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. / A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank. In: Nature Communications. 2020 ; Vol. 11, No. 1.

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Shen, X, Howard, DM, Adams, MJ, Hill, WD, Clarke, TK, McIntosh, AM, Deary, IJ, Whalley, HC & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium 2020, 'A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank', Nature Communications, vol. 11, no. 1, 2301. https://doi.org/10.1038/s41467-020-16022-0

A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank. / Shen, Xueyi; Howard, David M.; Adams, Mark J.; Hill, W. David; Clarke, Toni Kim; McIntosh, Andrew M.; Deary, Ian J.; Whalley, Heather C.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

In: Nature Communications, Vol. 11, No. 1, 2301, 01.12.2020.

Research output: Contribution to journal › Article › Academic › peer-review

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AU - Shen, Xueyi

AU - Howard, David M.

AU - Adams, Mark J.

AU - Hill, W. David

AU - Clarke, Toni Kim

AU - McIntosh, Andrew M.

AU - Deary, Ian J.

AU - Wray, Naomi R.

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AU - Abdellaoui, Abdel

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AU - Andlauer, Till F.M.

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AU - Beekman, Aartjan T.F.

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AU - Binder, Elisabeth B.

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AU - Cai, Na

AU - Castelao, Enrique

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AU - Coleman, Jonathan R.I.

AU - Colodro-Conde, Lucía

AU - Couvy-Duchesne, Baptiste

AU - Craddock, Nick

AU - Crawford, Gregory E.

AU - Davies, Gail

AU - Degenhardt, Franziska

AU - Derks, Eske M.

AU - Direk, Nese

AU - Dolan, Conor V.

AU - Dunn, Erin C.

AU - Eley, Thalia C.

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AU - Foo, Jerome C.

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AU - Uher, Rudolf

AU - Völzke, Henry

AU - Weissman, Myrna M.

AU - Werge, Thomas

AU - Lewis, Cathryn M.

AU - Levinson, Douglas F.

AU - Breen, Gerome

AU - Børglum, Anders D.

AU - Sullivan, Patrick F.

AU - Whalley, Heather C.

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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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DO - 10.1038/s41467-020-16022-0

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JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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