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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Abstract

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

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Figure 1: Evidence for genome-wide pleiotropy between psychiatric disorders.
Figure 2: Genomic partitioning of SNP-based heritability and SNP-based coheritability by annotation.
Figure 3: SNP-based heritabilities and coheritabilities.

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Acknowledgements

This research was directly supported by the Australian Research Council (FT0991360 and DE130100614) and the Australian National Health and Medical Research Council (613608, 1011506 and 1047956). The PGC Cross-Disorder Group is supported by National Institute of Mental Health (NIMH) grant U01 MH085520. Statistical analyses were carried out on the Genetic Cluster Computer (see URLs), which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003; principal investigator D.P.) along with a supplement from the Dutch Brain Foundation and VU University. Numerous (>100) grants from government agencies along with substantial private and foundation support worldwide enabled the collection of phenotype and genotype data, without which this research would not be possible; grant numbers are listed in primary PGC publications or in the Supplementary Note.

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Project conception: K.S.K., N.R.W. and J.W.S. Analysis: S.H.L. and N.R.W. Writing of the manuscript: N.R.W., S.H.L., K.S.K. and S.V.F. Quality control for PGC data: S. Ripke and B.M.N. Revisions to the manuscript: S.M.P., J.W.S., R.H.P., B.J.M., P.F.S., A.T., C.O., M.J.D., R.D.O. and J.B. Statistical advice: M.E.G. and J.S.W. Data access: D.P. PGC Workgroup Chairs: M.J.D. (analysis), S.V.F. (ADHD), M.J.D. and B.D. (co-chairs ASD), J.K. and P. Sklar (co-chairs bipolar disorder), P.F.S. (major depressive disorder), M.C.O. (schizophrenia) and J.W.S. and K.S.K. (co-chairs cross-disorder group). Collection, genotyping and analysis for PGC Working Groups. PGC ADHD Working Group: B.M.N., S.V.F., A.T., R.A., P.A., T. Banaschewski, M. Bayés, J.B., J.K.B., M.C., B.C., J.C., A.E.D., R.P.E., J.E., B.F., C.M.F., L. Kent, J.K., K.-P.L., S.K.L., J.M., J.J.M., S.E.M., J.M.S., A. Miranda, S.F.N., R.D.O., J.A.R.-Q., A. Reif, M. Ribasés, H.R., A. Rothenberger, J.A.S., R.S., S.L. Smalley, E.J.S.S.-B., H.-C.S., A.A.T. and N.W. PGC ASD Working Group: R.A., D.E.A., A.J.B., A.B., C.B., J.D. Buxbaum, A. Chakravarti, E.H.C., H.C., M.L.C., G.D., E.D., S.E., E.F., C.M.F., L. Gallagher, D.H.G., M. Gill, D.E.G., J.L.H., H.H., J.H., V.H., S.M.K., L. Klei, D.H. Ledbetter, C. Lord, J.K.L., E.M., S.M.M., C.L.M., W.M.M., A.P.M., D.M.-D.-L., E.M.M., M. Murtha, G.O., A.P., J.R.P., A.D.P., M.A.P.-V., J. Piven, F.P., K. Rehnström, K. Roeder, G.R., S.J.S., S.L. Santangelo, G.D.S., S.W.S., M. State, J.S. Sutcliffe, P. Szatmari, A.M.V., V.J.V., C.A.W., T.H.W., E.M.W., A.J.W., T.W.Y., B.D. and M.J.D. PGC BPD Working Group: S.M.P., D.A., H.A., O.A.A., A.A., L.B., J.A.B., J.D. Barchas, T.B.B., N.B., M. Bauer, F.B., S.E.B., W.B., D.H.R.B., C.S.B., M. Boehnke, G.B., R. Breuer, W.E.B., W.F.B., S. Caesar, K. Chambert, S. Cichon, D.A.C., A. Corvin, W.H.C., D.W.C., R.D., F. Degenhardt, S. Djurovic, F. Dudbridge, H.J.E., B.E., A.E.F., I.N.F., M. Flickinger, T.F., J.F., C.F., L.F., E.S.G., M. Gill, K.G.-S., E.K.G., T.A.G., D.G., W.G., H.G., M.L.H., M. Hautzinger, S. Herms, M. Hipolito, P.A.H., C.M.H., S.J., E.G.J., I.J., L.J., R. Kandaswamy, J.L.K., G.K.K., D.L.K., P.K., M. Landén, N.L., M. Lathrop, J. Lawrence, W.B.L., M. Leboyer, P.H.L., J. Li, P.L., D.-Y.L., C. Liu, F.W.L., S.L., P.B.M., W.M., N.G.M., M. Mattheisen, K.M., M. Mattingsdal, K.A.M., P.M., M.G.M., A. McIntosh, R.M., A.W.M., F.J.M., A. McQuillin, S.M., I.M., F.M., G.W.M., J.L.M., G.M., D.W.M., V. Moskvina, P.M., T.W.M., W.J.M., B.M.-M., R.M.M., C.M.N., I.N., V.N., M.M.N., J.I.N., E.A.N., C.O., U.O., M.J.O., B.S.P., J.B.P., P.P., E.M.Q., S. Raychaudhuri, A. Reif, J.P.R., M. Rietschel, D. Ruderfer, M. Schalling, A.F.S., W.A.S., N.J.S., T.G.S., J. Schumacher, M. Schwarz, E.S., L.J.S., P.D.S., E.N.S., D.S.C., M. Steffens, J.S. Strauss, J. Strohmaier, S.S., R.C.T., F.T., J.T., J.B.V., S.J.W., T.F.W., S.H.W., W.X., A.H.Y., P.P.Z., P.Z., S. Zöllner, J.R.K., P. Sklar, M.J.D., M.C.O. and N.C. PGC MDD Working Group: M.R.B., T. Bettecken, E.B.B., D.H.R.B., D.I.B., G.B., R. Breuer, S. Cichon, W.H.C., I.W.C., D. Czamara, E.J.D.G., F. Degenhardt, A.E.F., J.F., S.D.G., M. Gross, S.P.H., A.C.H., A.K.H., S. Herms, I.B.H., F.H., W.J.H., S. Hoefels, J.-J.H., M.I., I.J., L.J., J.-Y. T., J.A.K., M.A.K., A.K., W.B.L., D.F.L., C.M.L., D.-Y.L., S.L., D.J.M., P.A.F.M., W.M.,. N.G.M., M. Mattheisen, P.J.M., P.M., A. McIntosh, A.W.M., C.M.M., L.M., G.W.M., P.M., B.M.-M., W.A.N., M.M.N., D.R.N., B.W.P., M.L.P., J.B.P., M. Rietschel, W.A.S., T.G.S., J. Shi, S.I.S., S.L. Slager, J.H.S., M. Steffens, F.T., J.T., M.U., E.J.C.G.v.d.O., G.V.G., M.M.W., G.W., F.G.Z., P.F.S. and N.R.W. PGC SCZ Working Group: S. Ripke, B.M.N., S.M.P., B.J.M., I.A., F.A., O.A.A., M.H.A., N.B., D.W.B., D.H.R.B., R. Bruggeman, N.G.B., W.F.B., W.C., R.M.C., K. Choudhury, S. Cichon, C.R.C., P.C., A. Corvin, D. Curtis, S. Datta, S. Djurovic, G.J.D., J.D., F. Dudbridge, A.F., R.F., N.B.F., M. Friedl, P.V.G., L. Georgieva, I.G., M. Gill, H.G., L.D.H., M.L.H., T.F.H., A.M.H., P.A.H., C.M.H., A.I., A.K.K, R.S.K., M.C.K., E.K., Y.K., G.K.K., B.K., L. Krabbendam, R. Krasucki, J. Lawrence, P.H.L., T.L., D.F.L., J.A.L., D.-Y.L., D.H. Linszen, P.K.E.M., W.M., A.K.M., M. Mattheisen, M. Mattingsdal, S.M., S.A.M., A. McIntosh, A. McQuillin, H.M., I.M., V. Milanova, D.W.M., V. Moskvina, I.M.-G., M.M.N., C.O., A.O., L.O., R.A.O., M.J.O., C.N.P., M.T.P., B.S.P., J. Pimm, D.P., V.P., D.J.Q., H.B.R., M. Rietschel, L.R., D. Ruderfer, D. Rujescu, A.R.S., T.G.S., J. Shi, J.M.S., D.S.C., T.S.S., S.T., J.V.O., P.M.V., T.W., S. Zammit, P. Sklar, M.J.D., M.C.O., N.C., P.F.S. and K.S.K. PGC Cross-Disorder Group Working Group: S.H.L., S. Ripke, B.M.N., S.M.P., R.H.P., A.T., A.F., M.C.N., J.I.N., B.W.P., M. Rietschel, T.G.S., N.C., S.L. Santangelo, P.F.S., J.W.S., K.S.K. and N.R.W. PGC Analysis Working Group: S.H.L., S. Ripke, B.M.N., S.M.P., V.A., E.M.B., P.H.L., S.E.M., M.C.N., D.P., M.J.D. and N.R.W.

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Correspondence to Naomi R Wray.

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A list of members appears in the Supplementary Note.

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Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45, 984–994 (2013). https://doi.org/10.1038/ng.2711

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