Common variant at 16p11.2 conferring risk of psychosis

S Steinberg; S de Jong; M Mattheisen; J Costas; D Demontis; S Jamain; O P H Pietiläinen; K Lin; S Papiol; J Huttenlocher; E Sigurdsson; E Vassos; I Giegling; R Breuer; G Fraser; N Walker; I Melle; S Djurovic; I Agartz; A Tuulio-Henriksson; J Suvisaari; J Lönnqvist; T Paunio; L Olsen; T Hansen; A Ingason; M Pirinen; E Strengman; GROUP; D M Hougaard; T Orntoft; M Didriksen; M V Hollegaard; M Nordentoft; L Abramova; V Kaleda; M Arrojo; J Sanjuán; C Arango; B Etain; F Bellivier; A Méary; F Schürhoff; A Szoke; M Ribolsi; V Magni; A Siracusano; S Sperling; M Rossner; C Christiansen; L A Kiemeney; B Franke; L H van den Berg; J Veldink; S Curran; P Bolton; M Poot; W Staal; K Rehnstrom; H Kilpinen; C M Freitag; J Meyer; P Magnusson; E Saemundsen; I Martsenkovsky; I Bikshaieva; I Martsenkovska; O Vashchenko; M Raleva; K Paketchieva; B Stefanovski; N Durmishi; M Pejovic Milovancevic; D Lecic Tosevski; T Silagadze; N Naneishvili; N Mikeladze; S Surguladze; J B Vincent; A Farmer; P B Mitchell; A Wright; P R Schofield; J M Fullerton; G W Montgomery; N G Martin; I A Rubino; R van Winkel; G Kenis; M De Hert; J M Réthelyi; I Bitter; L Terenius; E G Jönsson; S Bakker; J van Os; A Jablensky; M Leboyer; E Bramon; J Powell; R Murray; A Corvin; M Gill; D Morris; F A O'Neill; K Kendler; B Riley; Wellcome Trust Case Control Consortium 2; N Craddock; M J Owen; M C O'Donovan; U Thorsteinsdottir; A Kong; H Ehrenreich; A Carracedo; V Golimbet; O A Andreassen; A D Børglum; O Mors; P B Mortensen; T Werge; R A Ophoff; M M Nöthen; M Rietschel; S Cichon; M Ruggeri; S Tosato; A Palotie; D St Clair; D Rujescu; D A Collier; H Stefansson; K Stefansson

doi:10.1038/mp.2012.157

Common variant at 16p11.2 conferring risk of psychosis

Mol Psychiatry. 2014 Jan;19(1):108-14. doi: 10.1038/mp.2012.157. Epub 2012 Nov 20.

Authors

S Steinberg¹, S de Jong², M Mattheisen³, J Costas⁴, D Demontis⁵, S Jamain⁶, O P H Pietiläinen⁷, K Lin⁸, S Papiol⁹, J Huttenlocher¹⁰, E Sigurdsson¹¹, E Vassos¹², I Giegling¹³, R Breuer¹⁴, G Fraser¹⁵, N Walker¹⁶, I Melle¹⁷, S Djurovic¹⁷, I Agartz¹⁷, A Tuulio-Henriksson¹⁸, J Suvisaari¹⁸, J Lönnqvist¹⁸, T Paunio¹⁹, L Olsen²⁰, T Hansen²⁰, A Ingason²⁰, M Pirinen²¹, E Strengman²²; GROUP; D M Hougaard²³, T Orntoft²⁴, M Didriksen²⁵, M V Hollegaard²³, M Nordentoft²⁶, L Abramova²⁷, V Kaleda²⁷, M Arrojo²⁸, J Sanjuán²⁹, C Arango³⁰, B Etain³¹, F Bellivier³², A Méary³¹, F Schürhoff³², A Szoke³¹, M Ribolsi³³, V Magni³³, A Siracusano³³, S Sperling³⁴, M Rossner³⁵, C Christiansen³⁶, L A Kiemeney³⁷, B Franke³⁸, L H van den Berg³⁹, J Veldink³⁹, S Curran⁴⁰, P Bolton⁴⁰, M Poot²², W Staal⁴¹, K Rehnstrom⁴², H Kilpinen⁴², C M Freitag⁴³, J Meyer⁴⁴, P Magnusson⁴⁵, E Saemundsen⁴⁶, I Martsenkovsky⁴⁷, I Bikshaieva⁴⁷, I Martsenkovska⁴⁷, O Vashchenko⁴⁷, M Raleva⁴⁸, K Paketchieva⁴⁸, B Stefanovski⁴⁸, N Durmishi⁴⁸, M Pejovic Milovancevic⁴⁹, D Lecic Tosevski⁴⁹, T Silagadze⁵⁰, N Naneishvili⁵⁰, N Mikeladze⁵⁰, S Surguladze⁵¹, J B Vincent⁵², A Farmer¹², P B Mitchell⁵³, A Wright⁵³, P R Schofield⁵⁴, J M Fullerton⁵⁴, G W Montgomery⁵⁵, N G Martin⁵⁵, I A Rubino³³, R van Winkel⁵⁶, G Kenis⁵⁷, M De Hert⁵⁸, J M Réthelyi⁵⁹, I Bitter⁵⁹, L Terenius⁶⁰, E G Jönsson⁶⁰, S Bakker⁶¹, J van Os⁶², A Jablensky⁶³, M Leboyer³², E Bramon⁶⁴, J Powell⁸, R Murray⁶⁵, A Corvin⁶⁶, M Gill⁶⁶, D Morris⁶⁶, F A O'Neill⁶⁷, K Kendler⁶⁸, B Riley⁶⁸; Wellcome Trust Case Control Consortium 2; N Craddock⁶⁹, M J Owen⁶⁹, M C O'Donovan⁶⁹, U Thorsteinsdottir⁷⁰, A Kong¹, H Ehrenreich⁹, A Carracedo⁷¹, V Golimbet²⁷, O A Andreassen¹⁷, A D Børglum⁷², O Mors⁷³, P B Mortensen⁷⁴, T Werge⁷⁵, R A Ophoff⁷⁶, M M Nöthen⁷⁷, M Rietschel¹⁴, S Cichon⁷⁸, M Ruggeri⁷⁹, S Tosato⁷⁹, A Palotie⁸⁰, D St Clair¹⁵, D Rujescu⁸¹, D A Collier⁸², H Stefansson¹, K Stefansson⁷⁰

Collaborators

Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly, S Steinberg, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso, Panos Deloukas, Christopher G Mathew, Jenefer M Blackwell, Matthew A Brown, Aiden Corvin, Chris C A Spencer

Affiliations

¹ deCODE genetics, Reykjavik, Iceland.
² Center for Neurobehavioral Genetics, UCLA, Los Angeles, CA, USA.
³ 1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Institute for Genomic Mathematics, University of Bonn, Bonn, Germany [3] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
⁴ Galician Foundation of Genomic Medicine-SERGAS, Complexo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela, Spain.
⁵ 1] Department of Biomedicine, Human Genetics, and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark [2] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
⁶ 1] Fondation FondaMental, Créteil, France [2] INSERM U 955, Psychiatrie Génétique, Créteil, France.
⁷ 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Institute for Health and Welfare, Public Health Genomics Unit, Helsinki, Finland [3] Wellcome Trust Sanger Institute, Cambridge, UK.
⁸ Department of Neuroscience, NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College, London, UK.
⁹ 1] DFG Research Center for Molecular Physiology of the Brain (CMPB), Göttingen, Germany [2] Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
¹⁰ 1] deCODE genetics, Reykjavik, Iceland [2] Department of Medical Genetics, Institute of Human Genetics, University of Tübingen, Tübingen, Germany.
¹¹ 1] Department of Psychiatry, National University Hospital, Reykjavik, Iceland [2] School of Medicine, University of Iceland, Reykjavik, Iceland.
¹² Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London, UK.
¹³ Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany.
¹⁴ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
¹⁵ Department of Mental Health, University of Aberdeen, Royal Cornhill Hospital, Aberdeen, UK.
¹⁶ Ravenscraig Hospital, Greenock, UK.
¹⁷ Division of Mental Health and Addiction, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo University Hospital, Oslo, Norway.
¹⁸ Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland, and Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
¹⁹ Public Health Genomics Unit, National Institute for Health and Welfare THL, Helsinki, Finland, and Department of Psychiatry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
²⁰ Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Copenhagen University, Roskilde, Denmark.
²¹ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
²² Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
²³ Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
²⁴ Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
²⁵ Synaptic transmission, H. Lundbeck A/S, Copenhagen, Denmark.
²⁶ 1] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark [2] Psychiatric Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
²⁷ Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia.
²⁸ Service of Psychiatry, Complexo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela, Spain.
²⁹ Unit of Psychiatry, Faculty of Medicine, University of Valencia, Network Center of Biomedical Research on Mental Health (CIBERSAM), Valencia, Spain.
³⁰ Hospital General Universitario Gregorio Marañón, IiSGM, Universidad Complutense, CIBERSAM, Madrid, Spain.
³¹ 1] Fondation FondaMental, Créteil, France [2] INSERM U 955, Psychiatrie Génétique, Créteil, France [3] AP-HP, Hôpital H. Mondor - A. Chenevier, Pôle de Psychiatrie, Creteil France.
³² 1] Fondation FondaMental, Créteil, France [2] INSERM U 955, Psychiatrie Génétique, Créteil, France [3] AP-HP, Hôpital H. Mondor - A. Chenevier, Pôle de Psychiatrie, Creteil France [4] Université Paris Est, Faculté de Médecine, Creteil, France.
³³ Section of Psychiatry, Department of Neuroscience, University of Rome-Tor Vergata, Rome, Italy.
³⁴ Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
³⁵ 1] DFG Research Center for Molecular Physiology of the Brain (CMPB), Göttingen, Germany [2] Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
³⁶ Nordic Bioscience, Herlev, Denmark.
³⁷ Department of Epidemiology and Biostatistics and Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
³⁸ Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
³⁹ Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands.
⁴⁰ 1] Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London, UK [2] Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College, London UK.
⁴¹ Department of Cognitive Neuroscience, Radboud University Nijmegen, Nijmegen, The Netherlands.
⁴² 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Wellcome Trust Sanger Institute, Cambridge, UK.
⁴³ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Frankfurt am Main, Frankfurt am Main, Germany.
⁴⁴ Department of Neurobehavioural Genetics, University of Trier, Trier, Germany.
⁴⁵ Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, Iceland.
⁴⁶ State Diagnostic and Counseling Centre, Kopavogur, Iceland.
⁴⁷ Department of Child, Adolescent Psychiatry and Medical-Social Rehabilitation, Ukrainian Research Institute of Social, Forensic Psychiatry and Drug Abuse, Kyiv, Ukraine.
⁴⁸ Department of Child and Adolescent Psychiatry, University of Skopje, Skopje, Macedonia.
⁴⁹ 1] Institute of Mental Health, Belgrade, Serbia [2] Medical Faculty, University of Belgrade, Belgrade, Serbia.
⁵⁰ Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia.
⁵¹ Social and Affective Neuroscience Lab, Ilia State University, Tbilisi, Georgia.
⁵² Molecular Neuropsychiatry and Development Laboratory, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
⁵³ 1] Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia [2] School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
⁵⁴ 1] Neuroscience Research Australia, Barker Street, Sydney, NSW, Australia [2] School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
⁵⁵ Queensland Institute of Medical Research, Brisbane, QLD, Australia.
⁵⁶ 1] University Psychiatric Center, Catholic University Leuven, Kortenberg, Belgium [2] Department of Psychiatry and Psychology, School of Mental Health and Neuroscience, European Graduate School of Neuroscience (EURON), South Limburg Mental Health Research and Teaching Network (SEARCH), Maastricht University Medical Center, Maastricht, The Netherlands.
⁵⁷ Department of Psychiatry and Psychology, School of Mental Health and Neuroscience, European Graduate School of Neuroscience (EURON), South Limburg Mental Health Research and Teaching Network (SEARCH), Maastricht University Medical Center, Maastricht, The Netherlands.
⁵⁸ University Psychiatric Center, Catholic University Leuven, Kortenberg, Belgium.
⁵⁹ Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.
⁶⁰ Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, Stockholm, Sweden.
⁶¹ Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center, Utrecht, The Netherlands.
⁶² Department of Psychiatry, Maastricht University Medical Centre, Maastricht, The Netherlands.
⁶³ Centre for Clinical Research in Neuropsychiatry (CCRN), Graylands Hospital, the University of Western Australia, Perth, WA, Australia.
⁶⁴ Mental Health Sciences Unit and Institute of Cognitive Neuroscience, University College London, London, UK.
⁶⁵ Department of Psychosis Studies, NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College, London, UK.
⁶⁶ Neuropsychiatric Genetics Research Group, School of Medicine, Trinity College, Dublin, Ireland.
⁶⁷ Department of Psychiatry, Queens University, Belfast, UK.
⁶⁸ 1] Department of Human Genetics, Virginia Commonwealth University, Richmond, VA, USA [2] Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA [3] Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
⁶⁹ MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.
⁷⁰ 1] deCODE genetics, Reykjavik, Iceland [2] School of Medicine, University of Iceland, Reykjavik, Iceland.
⁷¹ Genomic Medicine Group - Galician Foundation of Genomic Medicine-Biomedical Network Research Centre on Rare Diseases (CIBERER), University of Santiago de Compostela, Santiago de Compostela, Spain.
⁷² 1] Department of Biomedicine, Human Genetics, and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark [2] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark [3] Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
⁷³ 1] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark [2] Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
⁷⁴ 1] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark [2] National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
⁷⁵ 1] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark [2] Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Copenhagen University, Roskilde, Denmark.
⁷⁶ 1] Center for Neurobehavioral Genetics, UCLA, Los Angeles, CA, USA [2] Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center, Utrecht, The Netherlands.
⁷⁷ 1] German Center for Neurodegenerative Disorders (DZNE), Bonn Germany [2] Institute of Human Genetics, University of Bonn, Bonn Germany.
⁷⁸ 1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [2] Institute of Human Genetics, University of Bonn, Bonn Germany [3] Institute of Neurosciences and Medicine (INM-1), Juelich, Germany.
⁷⁹ Section of Psychiatry, University of Verona, Verona, Italy.
⁸⁰ 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Wellcome Trust Sanger Institute, Cambridge, UK [3] Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA [4] Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
⁸¹ 1] Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany [2] Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
⁸² 1] Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London, UK [2] Eli Lilly and Co. Ltd, Erl Wood Manor, Windlesham, Surrey, UK.

Abstract

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Bipolar Disorder / complications
Bipolar Disorder / epidemiology
Bipolar Disorder / genetics*
Chromosome Aberrations*
Chromosomes, Human, Pair 16 / genetics*
Europe
Female
Gene Expression Profiling
Genetic Predisposition to Disease*
Genome-Wide Association Study
Genotype
Humans
International Cooperation
Male
Middle Aged
Odds Ratio
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide / genetics*
Risk Factors
Schizophrenia / complications
Schizophrenia / epidemiology
Schizophrenia / genetics*
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding