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Open Access#22018
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection
Pardiñas, Antonio F; Holmans, Peter; Pocklington, Andrew J; Escott-Price, Valentina; Ripke, Stephan; Carrera, Noa; Legge, Sophie E; Bishop, Sophie
Pardiñas, Antonio F; Holmans, Peter; Pocklington, Andrew J; Escott-Price, Valentina; Ripke, Stephan; Carrera, Noa; Legge, Sophie E; Bishop, Sophie; Cameron, Darren; Hamshere, Marian L; Han, Jun; Hubbard, Leon; Lynham, Amy; Mantripragada, Kiran; Rees, Elliott; MacCabe, James H; McCarroll, Steven A; Baune, Bernhard T; Breen, Gerome; Byrne, Enda M; Dannlowski, Udo; Eley, Thalia C; Hayward, Caroline; Martin, Nicholas G; McIntosh, Andrew M; Plomin, Robert; 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, Esben; Als, Thomas D; Andreassen, Ole A; Bækvad-Hansen, Marie; Mortensen, Preben Bo; Pedersen, Carsten Bøcker; Børglum, Anders D; Bybjerg-Grauholm, Jonas; Djurovic, Srdjan; Durmishi, Naser; Pedersen, Marianne Giørtz; Golimbet, Vera; Grove, Jakob; Hougaard, David M
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files ; 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. ; European Union's Seventh Framework Programme Medical Research Council (MRC) Centre European Community's Seventh Framework Programme German Research Foundation (DFG) Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Munster National Health and Medical Research Council (NHMRC) Agencia Estatal de Investigacion (AEI) Xunta de Galicia Fondo Europeo de Desarrollo Regional (FEDER) Lundbeck Foundation Stanley Medical Research Institute, an advanced grant from the European Research Council Danish Strategic Research Council Aarhus University Wellcome Trust Juvenile Diabetes Research Foundation (JDRF) European Union National Institute for Health Research (NIHR) programme Chief Scientist Office of the Scottish government Health Directorates Scottish Funding Council National Institute of ...
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