Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
29483656
TITLE
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
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.
DATE PUBLISHED
2018 Feb 26
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2017/09/15
accepted 2018/01/07
entrez 2018/02/28 06:00
pubmed 2018/02/28 06:00
medline 2018/02/28 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Pardinas AF Pardinas Antonio F AF MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Holmans P Holmans Peter P MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Pocklington AJ Pocklington Andrew J AJ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Escott-Price V Escott-Price Valentina V MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Ripke S Ripke Stephan S Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany.
Carrera N Carrera Noa N MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Legge SE Legge Sophie E SE MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Bishop S Bishop Sophie S MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Cameron D Cameron Darren D MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Hamshere ML Hamshere Marian L ML MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Han J Han Jun J MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Hubbard L Hubbard Leon L MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Lynham A Lynham Amy A MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Mantripragada K Mantripragada Kiran K MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Rees E Rees Elliott E MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
MacCabe JH MacCabe James H JH Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
McCarroll SA McCarroll Steven A SA Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Baune BT Baune Bernhard T BT Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.
Breen G Breen Gerome G NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Byrne EM Byrne Enda M EM Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Dannlowski U Dannlowski Udo U Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
Eley TC Eley Thalia C TC MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Hayward C Hayward Caroline C Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
McIntosh AM McIntosh Andrew M AM Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Plomin R Plomin Robert R MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Porteous DJ Porteous David J DJ Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Wray NR Wray Naomi R NR Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Caballero A Caballero Armando A Departamento de Bioquímica, Genética e Inmunología. Facultad de Biología, Universidad de Vigo, Vigo, Spain.
Geschwind DH Geschwind Daniel H DH Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Huckins LM Huckins Laura M LM Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ruderfer DM Ruderfer Douglas M DM Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Santiago E Santiago Enrique E Departamento de Biología Funcional. Facultad de Biología, Universidad de Oviedo, Oviedo, Spain.
Sklar P Sklar Pamela P Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Stahl EA Stahl Eli A EA Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Won H Won Hyejung H Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Agerbo E Agerbo Esben E National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
Als TD Als Thomas D TD Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark.
Andreassen OA Andreassen Ole A OA NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Bækvad-Hansen M Bækvad-Hansen Marie M Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Mortensen PB Mortensen Preben Bo PB iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
Pedersen CB Pedersen Carsten Bøcker CB National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
Børglum AD Børglum Anders D AD Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark.
Bybjerg-Grauholm J Bybjerg-Grauholm Jonas J Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Djurovic S Djurovic Srdjan S Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Durmishi N Durmishi Naser N Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Macedonia.
Pedersen MG Pedersen Marianne Giørtz MG National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
Golimbet V Golimbet Vera V Department of Clinical Genetics, Mental Health Research Center, Moscow, Russia.
Grove J Grove Jakob J Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
Hougaard DM Hougaard David M DM Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Mattheisen M Mattheisen Manuel M Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark.
Molden E Molden Espen E Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
Mors O Mors Ole O Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
Nordentoft M Nordentoft Merete M Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
Pejovic-Milovancevic M Pejovic-Milovancevic Milica M Department of Psychiatry, School of Medicine, University of Belgrade, Belgrade, Serbia.
Sigurdsson E Sigurdsson Engilbert E Department of Psychiatry, National University Hospital, Reykjavik, Iceland.
Silagadze T Silagadze Teimuraz T Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia.
Hansen CS Hansen Christine Søholm CS Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Stefansson K Stefansson Kari K deCODE Genetics, Reykjavik, Iceland.
Stefansson H Stefansson Hreinn H deCODE Genetics, Reykjavik, Iceland.
Steinberg S Steinberg Stacy S deCODE Genetics, Reykjavik, Iceland.
Tosato S Tosato Sarah S Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
Werge T Werge Thomas T Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
GERAD1 Consortium:
CRESTAR Consortium:
Collier DA Collier David A DA Discovery Neuroscience Research, Eli Lilly and Company, Lilly Research Laboratories, Windlesham, UK.
Rujescu D Rujescu Dan D Department of Psychiatry, University of Munich, Munich, Germany.
Kirov G Kirov George G MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Owen MJ Owen Michael J MJ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. owenmj@cardiff.ac.uk.
O'Donovan MC O'Donovan Michael C MC MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. odonovanmc@cardiff.ac.uk.
Walters JTR Walters James T R JTR MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. waltersjt@cardiff.ac.uk.
GERAD1 Consortium
CRESTAR Consortium
GERAD1 Consortium
CRESTAR Consortium
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Harold Denise D
Sims Rebecca R
Gerrish Amy A
Chapman Jade J
Escott-Price Valentina V
Abraham Richard R
Hollingworth Paul P
Pahwa Jaspreet J
Denning Nicola N
Thomas Charlene C
Taylor Sarah S
Powell John J
Proitsi Petroula P
Lupton Michelle M
Lovestone Simon S
Passmore Peter P
Craig David D
McGuinness Bernadette B
Johnston Janet J
Todd Stephen S
Maier Wolfgang W
Jessen Frank F
Heun Reiner R
Schurmann Britta B
Ramirez Alfredo A
Becker Tim T
Herold Christine C
Lacour André A
Drichel Dmitriy D
Nothen Markus M
Goate Alison A
Cruchaga Carlos C
Nowotny Petra P
Morris John C JC
Mayo Kevin K
Holmans Peter P
O'Donovan Michael M
Owen Michael M
Williams Julie J
Achilla Evanthia E
Agerbo Esben E
Barr Cathy L CL
Böttger Theresa Wimberly TW
Breen Gerome G
Cohen Dan D
Collier David A DA
Curran Sarah S
Dempster Emma E
Dima Danai D
Sabes-Figuera Ramon R
Flanagan Robert J RJ
Frangou Sophia S
Frank Josef J
Gasse Christiane C
Gaughran Fiona F
Giegling Ina I
Grove Jakob J
Hannon Eilis E
Hartmann Annette M AM
Heißerer Barbara B
Helthuis Marinka M
Horsdal Henriette Thisted HT
Ingimarsson Oddur O
Jollie Karel K
Kennedy James L JL
Köhler Ole O
Konte Bettina B
Lang Maren M
Legge Sophie E SE
Lewis Cathryn C
MacCabe James J
Malhotra Anil K AK
McCrone Paul P
Meier Sandra M SM
Mill Jonathan J
Mors Ole O
Mortensen Preben Bo PB
Nöthen Markus M MM
O'Donovan Michael C MC
Owen Michael J MJ
Pardiñas Antonio F AF
Pedersen Carsten B CB
Rietschel Marcella M
Rujescu Dan D
Schwalber Ameli A
Sigurdsson Engilbert E
Sørensen Holger J HJ
Spencer Benjamin B
Stefansson Hreinn H
Støvring Henrik H
Strohmaier Jana J
Sullivan Patrick P
Vassos Evangelos E
Verbelen Moira M
Walters James T R JTR
Werge Thomas T
JOURNAL
VOLUME:
ISSUE:
TITLE: Nature genetics
ISOABBREVIATION: Nat. Genet.
YEAR: 2018
MONTH: Feb
DAY: 26
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1546-1718
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nat Genet
COUNTRY: United States
ISSNLINKING: 1061-4036
NLMUNIQUEID: 9216904
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
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