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).
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Acknowledgements
We would like to thank the subjects, their families and the recruitment centre staff. We would also like to acknowledge the help of Maria Dolores Moltó (Genetics Department, Valencia University, CIBERSAM), Eduardo Paz and Ramón Ramos-Ríos (Complexo Hospitalario de Santiago), and the contribution of Fundación Botín. This study makes use of seven external, publicly available data sets. First, it makes use of data generated by the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project whose principal investigators were Jeffrey A Lieberman, MD, T Scott Stroup, MD, MPH, and Joseph P McEvoy, MD. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. Second, the GAIN/BiGs data sets used in this work were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000017.v3.p1. Third, the study uses samples genotyped using the Ilumina 550K platform by the Pritzker Consortium, supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. The Pritzker Consortium includes scientists at the University of Michigan (H Akil and S J Watson, Site Directors, and Michael Boehnke, lead on bipolar genotyping effort); Stanford University (Rick Myers and Alan Schatzberg, Site Directors); the University of California at Davis (Ted Jones, Site Director); the University of California at Irvine (William Bunney, Site Director); and the Weill Medical College of Cornell University (Jack Barchas, Site Director). Fourth, the work uses data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) project, led by Gary Sachs, MD, and coordinated by Massachusetts General Hospital in Boston, MA (NIMH grant number was 2N01MH080001–001). Fifth, this study makes use of data generated by the Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. Sixth, we gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium* and the participating AGRE families. The AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M Lajonchere (PI). Seventh, the Autism Genome Project (AGP) data sets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number, phs000267.v1.p1. Submission of the data to dbGaP was provided by Dr Bernie Devlin on behalf of the AGP. Collection and submission of the data to dbGaP were supported by a grant from the Medical Research Council (G0601030) and the Wellcome Trust (075491/Z/04), Anthony P Monaco, PI, University of Oxford. This work was also supported by the European Union (grant numbers LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene), HEALTH-F2-2009-223423 (Project PsychCNVs), HEALTH-F4-2009-242257 (Project ADAMS) and IMI-JU-NewMeds); the National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) (grant numbers 01GS08144 (MooDS-Net) and 01GS08147 (NGFNplus)); the National Institute of Mental Health (R01 MH078075, and N01 MH900001, MH074027 to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project); the Centre of Excellence for Complex Disease Genetics of the Academy of Finland (grant numbers 213506 and 129680); the Biocentrum Helsinki Foundation and Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki; the Stanley Medical Research Institute; the Danish Council for Strategic Research (grant number 2101-07-0059); H Lundbeck A/S; the Research Council of Norway (grant number 163070/V50); the Danish Medical Research Council; the South-East Norway Health Authority (grant number 2004-123); the Medical Research Council; Ministerio de Sanidad y Consumo, Spain (grant number PI081522 to JC); Xunta de Galicia (grant number 08CSA005208PR to A Carracedo); the Swedish Research Council; the Wellcome Trust (Wellcome Trust grants 085475/B/08/Z and 085475/Z/08/Z as part of the Wellcome Trust Case Control Consortium 2); the Max Planck Society; Saarland University (grant number T6 03 10 00–45 to CMF); the Netherlands Foundation for Brain Research (Hersenstichting) (grant number 2008(1).34 to M Poot); and Eli Lilly and Company (genotyping for CATIE and part of the TOP sample). For further acknowledgements, see the Supplementary Material.
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Supplementary Information accompanies the paper on the Molecular Psychiatry website
Genetic Risk and Outcome in Psychosis (GROUP)
René S. Kahn1, Don H. Linszen2, Jim van Os3, Durk Wiersma4, Richard Bruggeman4, Wiepke Cahn1, Lieuwe de Haan2, Lydia Krabbendam3 and Inez Myin-Germeys3
1Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Postbus 85060, Utrecht, The Netherlands
2Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, NL326 Groot-Amsterdam, The Netherlands
3Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, 6229 HX Maastricht, The Netherlands
4University Medical Center Groningen, Department of Psychiatry, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
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Wellcome Trust Case Control Consortium 2
Wellcome Trust Case Control Consortium 2
Management committee
Peter Donnelly (Chair)1,2, Ines Barroso (Deputy Chair)3, Jenefer M Blackwell4,5, Elvira Bramon6, Matthew A Brown7, Juan P Casas8, Aiden Corvin9, Panos Deloukas3, Audrey Duncanson10, Janusz Jankowski11, Hugh S Markus12, Christopher G Mathew13, Colin NA Palmer14, Robert Plomin15, Anna Rautanen1, Stephen J Sawcer16, Richard C Trembath13, Ananth C Viswanathan17 and Nicholas W Wood18
Data and analysis group
Chris C A Spencer1, Gavin Band1, Céline Bellenguez1, Colin Freeman1, Garrett Hellenthal1, Eleni Giannoulatou1, Matti Pirinen1, Richard Pearson1, Amy Strange1, Zhan Su1, Damjan Vukcevic1 and Peter Donnelly1,2
DNA, genotyping, data QC and informatics group
Cordelia Langford3, Sarah E Hunt3, Sarah Edkins3, Rhian Gwilliam3, Hannah Blackburn3, Suzannah J Bumpstead3, Serge Dronov3, Matthew Gillman3, Emma Gray3, Naomi Hammond3, Alagurevathi Jayakumar3, Owen T McCann3, Jennifer Liddle3, Simon C Potter3, Radhi Ravindrarajah3, Michelle Ricketts3, Matthew Waller3, Paul Weston3, Sara Widaa3, Pamela Whittaker3, Ines Barroso3 and Panos Deloukas3.
Publications committee
Christopher G Mathew (Chair),13 Jenefer M Blackwell4,5, Matthew A Brown7, Aiden Corvin9 and Chris C A Spencer1
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
2Department of Statistics, University of Oxford, Oxford OX1 3TG, UK
3Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
4Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, 100 Roberts Road, Subiaco, Western Australia 6008, Australia
5Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 0XY, UK
6Department of Psychosis Studies, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London and The South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AF, UK
7University of Queensland Diamantina Institute, Brisbane, Queensland, Australia
8Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK, and Department Epidemiology and Public Health, University College London WC1E 6BT, UK
9Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
10Molecular and Physiological Sciences, The Wellcome Trust, London NW1 2BE, UK
11Department of Oncology, Old Road Campus, University of Oxford, Oxford OX3 7DQ, UK, Digestive Diseases Centre, Leicester Royal Infirmary, Leicester LE7 7HH, UK, and Centre for Digestive Diseases, Queen Mary University of London, London E1 2AD, UK
12Clinical Neurosciences, St George’s University of London, London SW17 0RE, UK
13King’s College London Dept Medical and Molecular Genetics, King’s Health Partners, Guy’s Hospital, London SE1 9RT, UK
14Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
15King’s College London Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK
16Department of Clinical Neurosciences, University of Cambridge Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
17NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK
18Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
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Steinberg, S., de Jong, S., Mattheisen, M. et al. Common variant at 16p11.2 conferring risk of psychosis. Mol Psychiatry 19, 108–114 (2014). https://doi.org/10.1038/mp.2012.157
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DOI: https://doi.org/10.1038/mp.2012.157
Keywords
- association
- bipolar disorder
- cross-disorder
- schizophrenia
- 16p11.2
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