TY - JOUR T1 - Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection JF - bioRxiv DO - 10.1101/068593 SP - 068593 AU - Antonio F. Pardiñas AU - Peter Holmans AU - Andrew J. Pocklington AU - Valentina Escott-Price AU - Stephan Ripke AU - Noa Carrera AU - Sophie E. Legge AU - Sophie Bishop AU - Darren Cameron AU - Marian L. Hamshere AU - Jun Han AU - Leon Hubbard AU - Amy Lynham AU - Kiran Mantripragada AU - Elliott Rees AU - James H. MacCabe AU - Steven A. McCarroll AU - Bernhard T. Baune AU - Gerome Breen AU - Enda M. Byrne AU - Udo Dannlowski AU - Thalia C. Eley AU - Caroline Hayward AU - Nicholas G. Martin AU - Andrew M. McIntosh AU - Robert Plomin AU - David J. Porteous AU - Naomi R. Wray AU - GERAD Consortium AU - David A. Collier AU - Dan Rujescu AU - George Kirov AU - Michael J. Owen AU - Michael C. O’Donovan AU - James T. R. Walters Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/08/09/068593.abstract N2 - 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 such insight. We report the largest single cohort genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data we identify 50 novel GWAS loci. Using gene-wide association statistics we implicate an additional set of 22 novel associations that map onto a single gene. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection. Associations point to novel areas of biology (e.g. metabotropic GABA-B signalling and acetyl cholinesterase), reinforce those implicated in earlier GWAS studies (e.g. calcium channel function), converge with earlier rare variants studies (e.g. NRXN1, GABAergic signalling), identify novel overlaps with autism (e.g. RBFOX1, FOXP1, FOXG1), and support early controversial candidate gene hypotheses (e.g. ERBB4 implicating neuregulin signalling). We also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. These findings provide novel 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 are maintained in the population. ER -