Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

A Publisher Correction to this article was published on 03 June 2019

This article has been updated

Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

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Fig. 1: Manhattan plot of schizophrenia GWAS associations.
Fig. 2: Partitioned heritability analysis of gene sets in schizophrenia.

Change history

  • 03 June 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

General. This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement 279227 (CRESTAR Consortium). The work at Cardiff University was funded by the Medical Research Council (MRC) Centre (MR/L010305/1), a program grant (G0800509) and a project grant (MR/L011794/1) and by the European Community’s Seventh Framework Programme HEALTH-F2-2010-241909 (project EU-GEI). U.D. received funding from the German Research Foundation (DFG, grant FOR2107 DA1151/5-1; SFB-TRR58, project C09) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17). E.M.B. and N.R.W. received salary funding from the National Health and Medical Research Council (NHMRC; 1078901, 105363). E. Santiago and A.C. received funding from the Agencia Estatal de Investigación (AEI; CGL2016-75904-C2-1-P), Xunta de Galicia (ED431C 2016-037) and Fondo Europeo de Desarrollo Regional (FEDER). The iPSYCH and GEMS2 teams acknowledge funding from the Lundbeck Foundation (grants R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an advanced grant from the European Research Council (project 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers.

Case data. We thank the participants and clinicians who took part in the CardiffCOGS study. For the CLOZUK2 sample, we thank Leyden Delta for supporting the sample collection, anonymization and data preparation (particularly M. Helthuis, J. Jansen, K. Jollie and A. Colson), Magna Laboratories, UK (A. Walker) and, for CLOZUK1, Novartis and the Doctor’s Laboratory staff for their guidance and cooperation. We acknowledge L. Bates, C. Bresner and L. Hopkins, at Cardiff University, for laboratory sample management. We acknowledge W. Lawrence and M. Einon, at Cardiff University, for support with the use and setup of computational infrastructures.

Control data. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium (WTCCC) data is available from its website. Funding for the project was provided by the Wellcome Trust under award 076113. The UK10K project was funded by Wellcome Trust award WT091310. Venous blood collection for the 1958 Birth Cohort (NCDS) was funded by UK MRC grant G0000934, peripheral blood lymphocyte preparation was funded by the Juvenile Diabetes Research Foundation (JDRF) and the Wellcome Trust, and cell line production, DNA extraction and processing were funded by Wellcome Trust grant 06854/Z/02/Z. Genotyping was supported by the Wellcome Trust (083270) and the European Union (ENGAGE: HEALTH-F4-2007-201413). The UK Blood Services Common Controls (UKBS-CC collection) was funded by the Wellcome Trust (076113/C/04/Z) and by a National Institute for Health Research (NIHR) programme grant to the NHS Blood and Transplant authority (NHSBT; RP-PG-0310-1002). NHSBT also made possible the recruitment of the Cardiff Controls, from participants who provided informed consent. Generation Scotland (GS) received core funding from the Chief Scientist Office of the Scottish government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the MRC and Wellcome Trust (grant 10436/Z/14/Z). The Type 1 Diabetes Genetics Consortium (T1DGC; EGA dataset EGAS00000000038) is a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF. The People of the British Isles project (POBI) is supported by the Wellcome Trust (088262/Z/09/Z). TwinsUK is funded by the Wellcome Trust, MRC, European Union, NIHR-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. Funding for the QIMR samples was provided by the Australian NHMRC (241944, 339462, 389875, 389891, 389892, 389927, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (FT0991360, FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (NIH; AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951) and the Center for Inherited Disease Research (Baltimore, MD, USA). TEDS is supported by a program grant from the MRC (G0901245-G0500079), with additional support from the NIH (HD044454, HD059215). In the GERAD1 Consortium, Cardiff University was supported by the Wellcome Trust, the MRC, Alzheimer’s Research UK (ARUK) and the Welsh government. King’s College London acknowledges support from the MRC. The University of Belfast acknowledges support from ARUK, the Alzheimer’s Society, Ulster Garden Villages, the Northern Ireland R&D Office and the Royal College of Physicians/Dunhill Medical Trust. Washington University was funded by NIH grants, the Barnes Jewish Foundation, and the Charles and Joanne Knight Alzheimer’s Research Initiative. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia and by the Alfried Krupp von Bohlen und Halbach-Stiftung.

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A.F.P. curated and processed genetic data, performed statistical analyses, contributed to the interpretation of results and participated in the primary drafting of the manuscript. P.H., A.J.P., V.E.-P., A.C. and E. Santiago performed statistical analyses, contributed to the interpretation of results and participated in the primary drafting of the manuscript. S.R. curated and processed genetic data and participated in the primary drafting of the manuscript. N.C. and M.L.H. contributed to the interpretation of results and participated in the primary drafting of the manuscript. S.E.L., S.B. and A.L. participated in the recruitment of participants for the study and curated and managed their phenotypic information. D.C., J.H., L.H., E.R. and G.K. contributed and curated data used in the statistical analyses. K.M. managed the laboratory and genotyping procedures at Cardiff University. J.H.M., D.A.C. and D.R. supervised the recruitment of the participants for the study. S.A.M. managed the genotyping of samples for the study. N.R.W. contributed genotypes of control samples and participated in the primary drafting of the manuscript. Control data were obtained from the GERAD1 Consortium; as such, the investigators within the GERAD1 Consortium contributed to the design and implementation of GERAD1 and/or provided control data but did not participate in analysis or writing of this report. D.H.G., L.M.H., D.M.R., P.S., E.A.S. and H.W. performed statistical analyses and contributed to the interpretation of results. M.J.O. and M.C.O’D. conceived and supervised the project, contributed to the interpretation of results and participated in the primary drafting of the manuscript. J.T.R.W. conceived and supervised the project, led the recruitment of the participants and sample acquisition for the study, performed statistical analysis, contributed to the interpretation of results and participated in the primary drafting of the manuscript. All other authors contributed genotypes of control samples or summary statistics of replication samples. All authors had the opportunity to review and comment on the manuscript, and all approved the final manuscript.

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Correspondence to Michael J. Owen or Michael C. O’Donovan or James T. R. Walters.

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D.A.C. is a full-time employee and stockholder of Eli Lilly and Company. The remaining authors declare no conflicts of interest.

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Gene sets that survive conditional analysis

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Pardiñas, A.F., Holmans, P., Pocklington, A.J. et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet 50, 381–389 (2018). https://doi.org/10.1038/s41588-018-0059-2

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