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

2.50
Hdl Handle:
http://hdl.handle.net/2336/620556
Title:
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection
Authors:
Pardiñas, Antonio F. ( 0000-0001-6845-7590 ) ; Holmans, Peter; Pocklington, Andrew J.; Escott-Price, Valentina; Ripke, Stephan ( 0000-0003-3622-835X ) ; Carrera, Noa; Legge, Sophie E. ( 0000-0001-6617-0289 ) ; Bishop, Sophie; Cameron, Darren ( 0000-0001-7520-7741 ) ; Hamshere, Marian L.; Han, Jun; Hubbard, Leon; Lynham, Amy ( 0000-0002-3189-6888 ) ; Mantripragada, Kiran; Rees, Elliott; MacCabe, James H. ( 0000-0002-6754-1018 ) ; McCarroll, Steven A.; Baune, Bernhard T. ( 0000-0001-6548-426X ) ; Breen, Gerome ( 0000-0003-2053-1792 ) ; Byrne, Enda M. ( 0000-0002-9491-7797 ) ; Dannlowski, Udo; Eley, Thalia C. ( 0000-0001-6458-0700 ) ; Hayward, Caroline ( 0000-0002-9405-9550 ) ; Martin, Nicholas G.; McIntosh, Andrew M. ( 0000-0002-0198-4588 ) ; Plomin, Robert; Porteous, David J. ( 0000-0003-1249-6106 ) ; Wray, Naomi R. ( 0000-0001-7421-3357 ) ; Caballero, Armando; Geschwind, Daniel H.; Huckins, Laura M. ( 0000-0002-5369-6502 ) ; Ruderfer, Douglas M.; Santiago, Enrique ( 0000-0002-5524-5641 ) ; Sklar, Pamela; Stahl, Eli A.; Won, Hyejung ( 0000-0003-3651-0566 ) ; Agerbo, Esben ( 0000-0002-2849-524X ) ; Als, Thomas D. ( 0000-0002-2963-1928 ) ; Andreassen, Ole A.; Bækvad-Hansen, Marie; Mortensen, Preben Bo; Pedersen, Carsten Bøcker; Børglum, Anders D.; Bybjerg-Grauholm, Jonas ( 0000-0003-1705-4008 ) ; Djurovic, Srdjan; Durmishi, Naser; Pedersen, Marianne Giørtz; Golimbet, Vera; Grove, Jakob ( 0000-0003-2284-5744 ) ; Hougaard, David M. ( 0000-0001-5928-3517 ) ; Mattheisen, Manuel; Molden, Espen ( 0000-0001-6190-2751 ) ; Mors, Ole; Nordentoft, Merete; Pejovic-Milovancevic, Milica; Sigurdsson, Engilbert ( 0000-0001-9404-7982 ) ; Silagadze, Teimuraz; Hansen, Christine Søholm ( 0000-0002-7518-4663 ) ; Stefansson, Kari; Stefansson, Hreinn; Steinberg, Stacy; Tosato, Sarah ( 0000-0002-9665-7538 ) ; Werge, Thomas; Collier, David A. ( 0000-0003-4087-1559 ) ; Rujescu, Dan; Kirov, George; Owen, Michael J. ( 0000-0003-4798-0862 ) ; O’Donovan, Michael C. ( 0000-0001-7073-2379 ) ; Walters, James T. R. ( 0000-0002-6980-4053 )
Citation:
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection 2018, 50 (3):381 Nature Genetics
Issue Date:
26-Feb-2018
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.
Description:
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
Additional Links:
http://www.nature.com/articles/s41588-018-0059-2
Rights:
Archived with thanks to Nature Genetics

Full metadata record

DC FieldValue Language
dc.contributor.authorPardiñas, Antonio F.en
dc.contributor.authorHolmans, Peteren
dc.contributor.authorPocklington, Andrew J.en
dc.contributor.authorEscott-Price, Valentinaen
dc.contributor.authorRipke, Stephanen
dc.contributor.authorCarrera, Noaen
dc.contributor.authorLegge, Sophie E.en
dc.contributor.authorBishop, Sophieen
dc.contributor.authorCameron, Darrenen
dc.contributor.authorHamshere, Marian L.en
dc.contributor.authorHan, Junen
dc.contributor.authorHubbard, Leonen
dc.contributor.authorLynham, Amyen
dc.contributor.authorMantripragada, Kiranen
dc.contributor.authorRees, Elliotten
dc.contributor.authorMacCabe, James H.en
dc.contributor.authorMcCarroll, Steven A.en
dc.contributor.authorBaune, Bernhard T.en
dc.contributor.authorBreen, Geromeen
dc.contributor.authorByrne, Enda M.en
dc.contributor.authorDannlowski, Udoen
dc.contributor.authorEley, Thalia C.en
dc.contributor.authorHayward, Carolineen
dc.contributor.authorMartin, Nicholas G.en
dc.contributor.authorMcIntosh, Andrew M.en
dc.contributor.authorPlomin, Roberten
dc.contributor.authorPorteous, David J.en
dc.contributor.authorWray, Naomi R.en
dc.contributor.authorCaballero, Armandoen
dc.contributor.authorGeschwind, Daniel H.en
dc.contributor.authorHuckins, Laura M.en
dc.contributor.authorRuderfer, Douglas M.en
dc.contributor.authorSantiago, Enriqueen
dc.contributor.authorSklar, Pamelaen
dc.contributor.authorStahl, Eli A.en
dc.contributor.authorWon, Hyejungen
dc.contributor.authorAgerbo, Esbenen
dc.contributor.authorAls, Thomas D.en
dc.contributor.authorAndreassen, Ole A.en
dc.contributor.authorBækvad-Hansen, Marieen
dc.contributor.authorMortensen, Preben Boen
dc.contributor.authorPedersen, Carsten Bøckeren
dc.contributor.authorBørglum, Anders D.en
dc.contributor.authorBybjerg-Grauholm, Jonasen
dc.contributor.authorDjurovic, Srdjanen
dc.contributor.authorDurmishi, Naseren
dc.contributor.authorPedersen, Marianne Giørtzen
dc.contributor.authorGolimbet, Veraen
dc.contributor.authorGrove, Jakoben
dc.contributor.authorHougaard, David M.en
dc.contributor.authorMattheisen, Manuelen
dc.contributor.authorMolden, Espenen
dc.contributor.authorMors, Oleen
dc.contributor.authorNordentoft, Mereteen
dc.contributor.authorPejovic-Milovancevic, Milicaen
dc.contributor.authorSigurdsson, Engilberten
dc.contributor.authorSilagadze, Teimurazen
dc.contributor.authorHansen, Christine Søholmen
dc.contributor.authorStefansson, Karien
dc.contributor.authorStefansson, Hreinnen
dc.contributor.authorSteinberg, Stacyen
dc.contributor.authorTosato, Sarahen
dc.contributor.authorWerge, Thomasen
dc.contributor.authorCollier, David A.en
dc.contributor.authorRujescu, Danen
dc.contributor.authorKirov, Georgeen
dc.contributor.authorOwen, Michael J.en
dc.contributor.authorO’Donovan, Michael C.en
dc.contributor.authorWalters, James T. R.en
dc.date.accessioned2018-05-07T14:20:22Z-
dc.date.available2018-05-07T14:20:22Z-
dc.date.issued2018-02-26-
dc.date.submitted2018-
dc.identifier.citationCommon schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection 2018, 50 (3):381 Nature Geneticsen
dc.identifier.issn1061-4036-
dc.identifier.issn1546-1718-
dc.identifier.doi10.1038/s41588-018-0059-2-
dc.identifier.urihttp://hdl.handle.net/2336/620556-
dc.descriptionTo 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 Filesen
dc.description.abstractSchizophrenia 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.en
dc.description.sponsorshipEuropean 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 Diabetes and Digestive and Kidney Diseases (NIDDK) National Institute of Allergy and Infectious Diseases (NIAID) National Human Genome Research Institute (NHGRI) National Institute of Child Health and Human Development (NICHD) JDRF NIHR King's College London Australian NHMRC Australian Research Council FP-5 GenomEUtwin Project US National Institutes of Health (NIH) Center for Inherited Disease Research (Baltimore, MD, USA) NIH Alzheimer's Research UK (ARUK) Welsh government ARUK Alzheimer's Society Ulster Garden Villages Northern Ireland RD Office Royal College of Physicians/Dunhill Medical Trust NIH Barnes Jewish Foundation Charles and Joanne Knight Alzheimer's Research Initiative German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia Alfried Krupp von Bohlen und Halbach-Stiftungen
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.relation.urlhttp://www.nature.com/articles/s41588-018-0059-2en
dc.rightsArchived with thanks to Nature Geneticsen
dc.subjectGeðklofien
dc.subjectGenarannsókniren
dc.subjectGenen
dc.subjectPSY12en
dc.subject.meshSchizophreniaen
dc.subject.meshGenome-Wide Association Studyen
dc.titleCommon schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selectionen
dc.typeArticleen
dc.contributor.departmentShow more [ 1 ] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Gen, Div Psychol Med & Clin Neurosci, Sch Med, Cardiff, S Glam, Wales Show more [ 2 ] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA Show more [ 3 ] Charite, Dept Psychiat & Psychotherapy, Campus Mitte, Berlin, Germany Show more [ 4 ] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, London, England Show more [ 5 ] MIT & Harvard, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA Show more [ 6 ] Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia Show more [ 7 ] Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC Social Genet & Dev Psychiat Ctr, London, England Show more [ 8 ] Kings Coll London, Maudsley Hosp, NIHR Biomed Res Ctr Mental Hlth, London, England Show more [ 9 ] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England Show more [ 10 ] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Show more [ 11 ] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia Show more [ 12 ] Univ Munster, Dept Psychiat Psychotherapy, Munster, Germany Show more [ 13 ] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh, Midlothian, Scotland Show more [ 14 ] Univ Queensland, Sch Psychol, Brisbane, Qld, Australia Show more [ 15 ] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia Show more [ 16 ] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland Show more [ 17 ] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland Show more [ 18 ] Univ Vigo, Fac Biol, Dept Bioqumi Genet & Inmunol, Vigo, Spain Show more [ 19 ] Calif State Univ Los Angeles, David Geffen Sch Med, Semel Inst, Ctr Autism Res & Treatment,Dept Neurol, Los Angeles, CA 90032 USA Show more [ 20 ] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Gen, New York, NY 10029 USA Show more [ 21 ] Univ Oviedo, Fac Biol, Dept Biol Func, Oviedo, Spain Show more [ 22 ] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Aarhus, Denmark Show more [ 23 ] Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark Show more [ 24 ] Aarhus Univ, Ctr Integrat Sequencing, iSEQ, Aarhus, Denmark Show more [ 25 ] Aarhus Univ, Dept Biomed Human Genet, Aarhus, Denmark Show more [ 26 ] Univ Oslo, Inst Clin Med, Oslo, Norway Show more [ 27 ] Oslo Univ Hosp, Div Mental Hlth & Addict, KG Jebsen Ctr Psychosis Res, NORMENT, Oslo, Norway Show more [ 28 ] Statens Serum Inst, Dept Congenital Disorders, Ctr Neonatal Screening, Copenhagen, Denmark Show more [ 29 ] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Psychosis Res, NORMENT, Bergen, Norway Show more [ 30 ] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway [ 31 ] Univ Clin Psychiat, Dept Child & Adolescent Psychiat, Skopje, Macedonia [ 32 ] Mental Hlth Res Ctr, Dept Clin Genet, Moscow, Russia Show more [ 33 ] Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark [ 34 ] Diakonhjemmet Hosp, Ctr Psychopharmacol, Oslo, Norway Show more [ 35 ] Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark Show more [ 36 ] Univ Copenhagen, Mental Hlth Ctr Copenhagen, Mental Hlth Serv Capital Reg Denmark, Copenhagen, Denmark Show more [ 37 ] Univ Belgrade, Sch Med, Dept Psychiat, Belgrade, Serbia Show more [ 38 ] Natl Univ Hosp Reykjavik, Dept Psychiat, Reykjavik, Iceland [ 39 ] TSMU, Dept Psychiat & Drug Addict, Tbilisi, Rep of Georgia [ 40 ] deCODE Genet, Reykjavik, Iceland Show more [ 41 ] Univ Verona, Dept Publ Hlth & Community Med, Sect Psychiat, Verona, Italy [ 42 ] Mental Hlth Serv Copenhagen, MHC Sct Hans, Inst Biol Psychiat, Roskilde, Denmark Show more [ 43 ] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark Show more [ 44 ] Eli Lilly & Co, Lilly Res Labs, Discovery Neurosci Res, Windlesham, Surrey, England Show more [ 45 ] Univ Halle, Dept Psychiat, Halle, Germany Show more [ 46 ] Univ Munich, Dept Psychiat, Munich, Germanyen
dc.identifier.journalNature Geneticsen
dc.rights.accessOpen Access - Opinn aðganguren
All Items in Hirsla are protected by copyright, with all rights reserved, unless otherwise indicated.