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

Pardinas, Antonio F. ORCID:, GERAD Consortium, Holmans, Peter ORCID:, Pocklington, Andrew J. ORCID:, Escott-Price, Valentina ORCID:, Ripke, Stephan, Carrera, Noa ORCID:, Legge, Sophie E., Bishop, Sophie, Cameron, Darren, Hamshere, Marian L. ORCID:, Han, Jun, Hubbard, Leon, Lynham, Amy ORCID:, Mantripragada, Kiran ORCID:, Rees, Elliott ORCID:, MacCabe, James H., McCarroll, Steven A., Baune, Bernhard T., Breen, Gerome, Byrne, Enda, Dannlowski, Udo, Eley, Thalia C., Hayward, Caroline, Martin, Nichols G., McIntosh, Andrew M., Plomin, Robert P., Porteous, David J., Wray, Naomi R., Caballero, Armando, Geschwind, Daniel H., Huckins, Laura M., Ruderfer, Douglas M., Santiago, Enrique, Sklar, Pamela, Stahl, Eli A., Won, Hyejung, Agerbo, Eeben A., Als, Thomas P., Andreassen, Ole A., Bækvad-Hansen, Marie, Mortensen, Preben Bo, Pedersen, Carsten Bocker, Børglum, Anders D., Bybjerg-Grauholm, Jonas, Djurovic, Srdjan, Durmishi, Naser, Giørtz Pedersenu, Marianne, Golimbet, Vera, Grove, Jakob, Hougaard, David M., Mattheisen, Manuel, Molden, Espen, Mors, Ole, Nordentoft, Merete, Pejovic-Milovancevic, Milica, Sigurdsson, Engilbert, Silagadze, Teimuraz, Søholm Hansen, Christine, Stefansson, Kari, Stefansson, Hreinn, Steinberg, Stacy, Tosato, Sarah, Werge, Thomas, Collier, David A., Rujescu, Dan, Kirov, George ORCID:, Owen, Michael J ORCID:, O'Donovan, Michael C. ORCID:, Walters, James T. R. ORCID:, Williams, Julie ORCID: and CRESTAR Consortium 2018. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics 50 , pp. 381-389. 10.1038/s41588-018-0059-2

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Julie Williams is a member of the GERAD1 Consortium
Publisher: Nature
ISSN: 1061-4036
Date of First Compliant Deposit: 1 February 2018
Date of Acceptance: 7 January 2018
Last Modified: 19 Jul 2024 05:22

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