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

Antonio F. Pardiñas, Peter Holmans, Andrew J. Pocklington, Valentina Escott-Price, Stephan Ripke, Noa Carrera, Sophie E. Legge, Sophie Bishop, Darren Cameron, Marian L. Hamshere, Jun Han, Leon Hubbard, Amy Lynham, Kiran Mantripragada, Elliott Rees, James H. MacCabe, Steven A. McCarroll, Bernhard T. Baune, Gerome Breen, Enda M. ByrneUdo Dannlowski, Thalia C. Eley, Caroline Hayward, Nicholas G. Martin, Andrew M. McIntosh, Robert Plomin, David J. Porteous, Naomi R. Wray, Armando Caballero, Daniel H. Geschwind, Laura M. Huckins, Douglas M. Ruderfer, Enrique Santiago, Pamela Sklar, Eli A. Stahl, Hyejung Won, Esben Agerbo, Thomas D. Als, Ole A. Andreassen, Marie Bækvad-Hansen, Preben Bo Mortensen, Carsten Bøcker Pedersen, Anders D. Børglum, Jonas Bybjerg-Grauholm, Srdjan Djurovic, Naser Durmishi, Marianne Giørtz Pedersen, Vera Golimbet, Jakob Grove, David M. Hougaard, Manuel Mattheisen, Espen Molden, Ole Mors, Merete Nordentoft, Milica Pejovic-Milovancevic, Engilbert Sigurdsson, Teimuraz Silagadze, Christine Søholm Hansen, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, Sarah Tosato, Thomas Werge, Denise Harold, Rebecca Sims, Amy Gerrish, Jade Chapman, Richard Abraham, Paul Hollingworth, Jaspreet Pahwa, Nicola Denning, Charlene Thomas, Sarah Taylor, John Powell, Petroula Proitsi, Michelle Lupton, Simon Lovestone, Peter Passmore, David Craig, Bernadette McGuinness, Janet Johnston, Stephen Todd, Wolfgang Maier, Frank Jessen, Reiner Heun, Britta Schurmann, Alfredo Ramirez, Tim Becker, Christine Herold, André Lacour, Dmitriy Drichel, Markus Nothen, Alison Goate, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Michael C. O'Donovan, Michael J. Owen, Julie Williams, Evanthia Achilla, Cathy L. Barr, Theresa Wimberly Böttger, Dan Cohen, Sarah Curran, Emma Dempster, Danai Dima, Ramon Sabes-Figuera, Robert J. Flanagan, Sophia Frangou, Josef Frank, Christiane Gasse, Fiona Gaughran, Ina Giegling, Eilis Hannon, Annette M. Hartmann, Barbara Heißerer, Marinka Helthuis, Henriette Thisted Horsdal, Oddur Ingimarsson, Karel Jollie, James L. Kennedy, Ole Köhler, Bettina Konte, Maren Lang, Cathryn Lewis, James MacCaba, Anil K. Malhotra, Paul McCrone, Sandra M. Meier, Jonathan Mill, Markus M. Nöthen, Carsten B. Pedersen, Marcella Rietschel, Dan Rujescu, Ameli Schwalber, Holger J. Sørensen, Benjamin Spencer, Henrik Støvring, Jana Strohmaier, Patrick Sullivan, Evangelos Vassos, Moira Verbelen, David A. Collier, George Kirov, James T.R. Walters

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628 Scopus citations

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.

Original languageEnglish
Pages (from-to)381-389
Number of pages9
JournalNature Genetics
Volume50
Issue number3
DOIs
StatePublished - Mar 1 2018

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