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Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

A Corrigendum to this article was published on 25 November 2015

A Corrigendum to this article was published on 26 May 2015

This article has been updated

Abstract

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

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Figure 1: Overview of statistical approach for integrative pathway analysis of GWAS data.
Figure 2: Quantile-quantile plot showing P-value distribution for a combined analysis combining results from five pathway analysis methods and six pathway databases.
Figure 3: Multidimensional scaling plot of top 50 pathways with suggestive (<0.
Figure 4: Gene coexpression networks across brain development and regions for genes in all pathways with FDR < 0.1.

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Gene Expression Omnibus

Change history

  • 19 January 2015

    In the version of this article initially published, the affiliation numbers given for several authors were incorrect. Astrid M. Vicente was listed as associated with affiliations 234–236 instead of 233–235, Veronica J. Vieland as 237 instead of 236, Kenneth S. Kendler as 110, 253 and 254 instead of 110, 252 and 253, and Zhaoming Zhao as 255 instead of 254 and 255. The errors have been corrected in the HTML and PDF versions of the article.

  • 28 April 2015

    In the version of this article initially published, the name of author Zhongming Zhao was misspelled Zhaoming Zhao. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. The PGC Cross-Disorder Group is supported by NIMH grant U01 MH085520. Statistical analyses were carried out on the Genetic Cluster Computer, 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.

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Project conception: G.B., P.F.S., P.A.H. Analysis: C.O'D., P.H.L., P.A.H., G.B., S.R., L.R., L.D., S.N. Writing of the manuscript: G.B., C.O'D. P.A.H., P.H.L., L.R., L.D., N.P. Quality control for PGC data: S. Ripke and B.M.N. Revisions to the manuscript: G.B., D.H.G., C.O'D., L.R., P.H.L., N.P. PGC Network and Pathway Analysis Workgroup: S.R., B.M.N., S.M.P., D.H.G., P.A.H., P.H.L., M.M., C.O'D., D.P., L.R., L.D., P.F.S., J.W.S., N.R.W., Z.Z. PGC Workgroup Chairs: M.J.D. (analysis), S.V.F. (ADHD), M.J.D. and B.D. (co-chairs ASD), G.B. and P.A.H. (Network and Pathway Analysis subgroup), J.K. and P. Sklar (co-chairs bipolar disorder), P.F.S. (major depressive disorder), M.C.O'D. (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., G.B., M.J.D. and N.R.W.

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Correspondence to Peter A Holmans or Gerome Breen.

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Competing interests

G.B. is a consultant in PreClinical Genetics at Eli Lilly.

Integrated supplementary information

Supplementary Figure 1 Observed and expected (shown as ranges representing 95% confidence intervals) number of significant pathways overlapping between different sets of results from different methods.

(a) Analysis conducted using the SCZ dataset, top 25% of each method. (b) Analysis conducted using the NULL dataset, top 25% of each method.

Supplementary Figure 2 Quantile-quantile plots summarizing combined p-values for each method on different phenotypes.

Order is (a) SCZ, (b) BIP, (c) MDD, (d) AUT, (e) ADD, (f) null data from permutations and, (g) HIV.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Analysis, and Supplementary Tables 1–4, 6 and 12–16 (PDF 280 kb)

Supplementary Methods Checklist (PDF 345 kb)

Supplementary Table 5

Pathway results for each disease/cross-disease dataset (XLS 21847 kb)

Supplementary Table 7

Ranked list of pathways when combined across 3 well-powered disease groups. (XLS 3804 kb)

Supplementary Table 8

Ranked list of pathways when combined across SCZ, HIV and NULL datasets. (XLS 3803 kb)

Supplementary Table 9

Details related to module-level summaries of spatial, temporal, and cell-type specific expression patterns. (XLSX 184 kb)

Supplementary Table 10

Ranked list of pathways when combined across all 5 disease groups. (XLS 3959 kb)

Supplementary Table 11

P values for the SNPs in each gene in each disorder and their pathways membership are presented for all pathways with q < 0.1. (XLSX 639 kb)

Supplementary Table 17

Information related to the supervised network analysis of 797 genes, specifying gene set membership from the 3 major pathways, module membership, and relative connectivity (kME) to each module. (XLSX 171 kb)

Supplementary Data

Source data for Figure 3 (ZIP 1200 kb)

Supplementary Software

PGC pathway network analysis code (TXT 22 kb)

Source data

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The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci 18, 199–209 (2015). https://doi.org/10.1038/nn.3922

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