Meta-Analysis

. 2016 Aug 1;25(15):3383-3394.

doi: 10.1093/hmg/ddw181. Epub 2016 Jun 21.

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Liping Hou¹, Sarah E Bergen^{2

3}, Nirmala Akula¹, Jie Song², Christina M Hultman², Mikael Landén^{4

2}, Mazda Adli⁵, Martin Alda⁶, Raffaella Ardau⁷, Bárbara Arias⁸, Jean-Michel Aubry⁹, Lena Backlund¹⁰, Judith A Badner¹¹, Thomas B Barrett¹², Michael Bauer¹³, Bernhard T Baune¹⁴, Frank Bellivier¹⁵, Antonio Benabarre¹⁶, Susanne Bengesser¹⁷, Wade H Berrettini¹⁸, Abesh Kumar Bhattacharjee¹⁹, Joanna M Biernacka^{20

21}, Armin Birner¹⁷, Cinnamon S Bloss²², Clara Brichant-Petitjean¹⁵, Elise T Bui¹, William Byerley²³, Pablo Cervantes²⁴, Caterina Chillotti⁷, Sven Cichon^{25

26

27

28}, Francesc Colom¹⁶, William Coryell²⁹, David W Craig³⁰, Cristiana Cruceanu³¹, Piotr M Czerski³², Tony Davis¹⁴, Alexandre Dayer⁹, Franziska Degenhardt^{25

26}, Maria Del Zompo³³, J Raymond DePaulo³⁴, Howard J Edenberg³⁵, Bruno Étain³⁶, Peter Falkai³⁷, Tatiana Foroud³⁸, Andreas J Forstner^{25

26}, Louise Frisén^{39

40}, Mark A Frye²¹, Janice M Fullerton^{41

42}, Sébastien Gard⁴³, Julie S Garnham⁶, Elliot S Gershon¹¹, Fernando S Goes³⁴, Tiffany A Greenwood¹⁹, Maria Grigoroiu-Serbanescu⁴⁴, Joanna Hauser³², Urs Heilbronner^{45

46}, Stefanie Heilmann-Heimbach^{25

26}, Stefan Herms^{25

26

28}, Maria Hipolito⁴⁷, Shashi Hitturlingappa¹⁴, Per Hoffmann^{25

26

27

28}, Andrea Hofmann^{25

26}, Stephane Jamain³⁶, Esther Jiménez¹⁶, Jean-Pierre Kahn⁴⁸, Layla Kassem¹, John R Kelsoe¹⁹, Sarah Kittel-Schneider⁴⁹, Sebastian Kliwicki⁵⁰, Daniel L Koller³⁸, Barbara König⁵¹, Nina Lackner¹⁷, Gonzalo Laje¹, Maren Lang⁵², Catharina Lavebratt¹⁰, William B Lawson⁴⁷, Marion Leboyer³⁶, Susan G Leckband⁵³, Chunyu Liu⁵⁴, Anna Maaser^{25

26}, Pamela B Mahon³⁴, Wolfgang Maier⁵⁵, Mario Maj⁵⁶, Mirko Manchia^{33

57}, Lina Martinsson³⁹, Michael J McCarthy⁵⁸, Susan L McElroy⁵⁹, Melvin G McInnis⁶⁰, Rebecca McKinney¹⁹, Philip B Mitchell⁶¹, Marina Mitjans⁸, Francis M Mondimore³⁴, Palmiero Monteleone^{56

62}, Thomas W Mühleisen^{25

26

27}, Caroline M Nievergelt¹⁹, Markus M Nöthen^{25

26}, Tomas Novák⁶³, John I Nurnberger Jr⁶⁴, Evaristus A Nwulia⁴⁷, Urban Ösby⁶⁵, Andrea Pfennig¹³, James B Potash⁶⁶, Peter Propping²⁵, Andreas Reif⁴⁹, Eva Reininghaus¹⁷, John Rice⁶⁷, Marcella Rietschel⁵², Guy A Rouleau⁶⁸, Janusz K Rybakowski⁵⁰, Martin Schalling¹⁰, William A Scheftner⁶⁹, Peter R Schofield^{42

70}, Nicholas J Schork²², Thomas G Schulze^{1

34

45

46

52}, Johannes Schumacher^{25

26}, Barbara W Schweizer³⁴, Giovanni Severino³³, Tatyana Shekhtman¹⁹, Paul D Shilling¹⁹, Christian Simhandl⁷¹, Claire M Slaney⁶, Erin N Smith²², Alessio Squassina³³, Thomas Stamm⁵, Pavla Stopkova⁶³, Fabian Streit⁵², Jana Strohmaier⁵², Szabolcs Szelinger³⁰, Sarah K Tighe⁶⁶, Alfonso Tortorella⁵⁶, Gustavo Turecki³¹, Eduard Vieta¹⁶, Julia Volkert⁴⁹, Stephanie H Witt⁵², Adam Wright⁶¹, Peter P Zandi⁷², Peng Zhang⁶⁰, Sebastian Zollner⁶⁰, Francis J McMahon⁷³

Affiliations

¹ Intramural Research Program, National Institute of Mental Health, National Institutes of Health,U.S. Department of Health & Human Services, Bethesda, MD, USA.
² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
⁵ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
⁶ Department of Psychiatry, Dalhousie University, Halifax, Canada.
⁷ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
⁸ Department of Biologia Animal, Unitat d'Antropologia (Dp. Biología Animal), Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM, Barcelona, Spain.
⁹ Department of Mental Health and Psychiatry, Mood Disorders Unit, Geneva University Hospitals, Geneva, Switzerland.
¹⁰ Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹¹ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
¹² Portland Veterans Affairs Medical Center, Portland, OR, USA.
¹³ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany.
¹⁴ Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
¹⁵ INSERM UMR-S 1144 - Université Paris Diderot. Pôle de Psychiatrie, AP-HP, Groupe Hospitalier Lariboisière-F. Widal, Paris, France.
¹⁶ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
¹⁷ Special Outpatient Center for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
¹⁸ Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
¹⁹ Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
²⁰ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
²¹ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²² Scripps Translational Science Institute, La Jolla, CA, USA.
²³ Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA.
²⁴ McGill University Health Centre, Mood Disorders Program, Montreal, QC, Canada.
²⁵ Institute of Human Genetics, University of Bonn, Germany.
²⁶ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
²⁷ Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Germany.
²⁸ Division of Medical Genetics and Department of Biomedicine, University of Basel, Switzerland.
²⁹ University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
³⁰ The Translational Genomics Research Institute, Phoenix, AZ, USA.
³¹ Douglas Mental Health University Institute, McGill University, Montreal, Canada.
³² Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
³³ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³⁵ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁶ INSERM U955, Psychiatrie translationnelle, Université Paris Est Créteil, Pôle de Psychiatrie et d'Addictologie, Hôpitaux Universitaires Henri Mondor, Créteil, France.
³⁷ Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
³⁸ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁹ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁴⁰ Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
⁴¹ Psychiatric Genetics, Neuroscience Research Australia, Sydney, Australia.
⁴² School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
⁴³ Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
⁴⁴ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁴⁵ Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
⁴⁶ Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
⁴⁷ Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC, USA.
⁴⁸ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
⁴⁹ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁵⁰ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁵¹ Department of Psychiatry and Psychotherapeuthic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁵² Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁵³ Department of Pharmacy, VA San Diego Healthcare System, San Diego, CA, USA.
⁵⁴ Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
⁵⁵ Department of Psychiatry, University of Bonn, Germany.
⁵⁶ Department of Psychiatry, University of Naples SUN, Naples, Italy.
⁵⁷ Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁵⁸ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁵⁹ Lindner Center of HOPE, University of Cincinnati College of Medicine, Mason, OH, USA.
⁶⁰ Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
⁶¹ School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, Australia.
⁶² Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
⁶³ National Institute of Mental Health, Klecany, Czech Republic.
⁶⁴ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶⁵ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁶⁶ Department of Psychiatry, Carver College of Medicine, University of Iowa School of Medicine, Iowa City, IA, USA.
⁶⁷ Department of Psychiatry, Washington University School of Medicine in St. Louis.
⁶⁸ Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
⁶⁹ Rush University Medical Center, Chicago, IL, USA.
⁷⁰ Mental Illness, Neuroscience Research Australia, Sydney, Australia.
⁷¹ Bipolar Center Wiener Neustadt, Wiener Neustadt, Austria and.
⁷² Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷³ Intramural Research Program, National Institute of Mental Health, National Institutes of Health,U.S. Department of Health & Human Services, Bethesda, MD, USA, mcmahonf@mail.nih.gov.

PMID: 27329760
PMCID: PMC5179929
DOI: 10.1093/hmg/ddw181

Meta-Analysis

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Liping Hou et al. Hum Mol Genet. 2016.

. 2016 Aug 1;25(15):3383-3394.

doi: 10.1093/hmg/ddw181. Epub 2016 Jun 21.

Authors

Affiliations

¹ Intramural Research Program, National Institute of Mental Health, National Institutes of Health,U.S. Department of Health & Human Services, Bethesda, MD, USA.
² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
⁵ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
⁶ Department of Psychiatry, Dalhousie University, Halifax, Canada.
⁷ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
⁸ Department of Biologia Animal, Unitat d'Antropologia (Dp. Biología Animal), Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM, Barcelona, Spain.
⁹ Department of Mental Health and Psychiatry, Mood Disorders Unit, Geneva University Hospitals, Geneva, Switzerland.
¹⁰ Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹¹ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
¹² Portland Veterans Affairs Medical Center, Portland, OR, USA.
¹³ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany.
¹⁴ Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
¹⁵ INSERM UMR-S 1144 - Université Paris Diderot. Pôle de Psychiatrie, AP-HP, Groupe Hospitalier Lariboisière-F. Widal, Paris, France.
¹⁶ Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
¹⁷ Special Outpatient Center for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
¹⁸ Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
¹⁹ Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
²⁰ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
²¹ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²² Scripps Translational Science Institute, La Jolla, CA, USA.
²³ Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA.
²⁴ McGill University Health Centre, Mood Disorders Program, Montreal, QC, Canada.
²⁵ Institute of Human Genetics, University of Bonn, Germany.
²⁶ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
²⁷ Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Germany.
²⁸ Division of Medical Genetics and Department of Biomedicine, University of Basel, Switzerland.
²⁹ University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
³⁰ The Translational Genomics Research Institute, Phoenix, AZ, USA.
³¹ Douglas Mental Health University Institute, McGill University, Montreal, Canada.
³² Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
³³ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³⁵ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁶ INSERM U955, Psychiatrie translationnelle, Université Paris Est Créteil, Pôle de Psychiatrie et d'Addictologie, Hôpitaux Universitaires Henri Mondor, Créteil, France.
³⁷ Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
³⁸ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁹ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁴⁰ Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
⁴¹ Psychiatric Genetics, Neuroscience Research Australia, Sydney, Australia.
⁴² School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
⁴³ Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
⁴⁴ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
⁴⁵ Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
⁴⁶ Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
⁴⁷ Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC, USA.
⁴⁸ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
⁴⁹ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
⁵⁰ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
⁵¹ Department of Psychiatry and Psychotherapeuthic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁵² Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁵³ Department of Pharmacy, VA San Diego Healthcare System, San Diego, CA, USA.
⁵⁴ Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
⁵⁵ Department of Psychiatry, University of Bonn, Germany.
⁵⁶ Department of Psychiatry, University of Naples SUN, Naples, Italy.
⁵⁷ Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁵⁸ Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
⁵⁹ Lindner Center of HOPE, University of Cincinnati College of Medicine, Mason, OH, USA.
⁶⁰ Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
⁶¹ School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, Australia.
⁶² Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
⁶³ National Institute of Mental Health, Klecany, Czech Republic.
⁶⁴ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶⁵ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁶⁶ Department of Psychiatry, Carver College of Medicine, University of Iowa School of Medicine, Iowa City, IA, USA.
⁶⁷ Department of Psychiatry, Washington University School of Medicine in St. Louis.
⁶⁸ Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
⁶⁹ Rush University Medical Center, Chicago, IL, USA.
⁷⁰ Mental Illness, Neuroscience Research Australia, Sydney, Australia.
⁷¹ Bipolar Center Wiener Neustadt, Wiener Neustadt, Austria and.
⁷² Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷³ Intramural Research Program, National Institute of Mental Health, National Institutes of Health,U.S. Department of Health & Human Services, Bethesda, MD, USA, mcmahonf@mail.nih.gov.

PMID: 27329760
PMCID: PMC5179929
DOI: 10.1093/hmg/ddw181

Abstract

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 ^- ⁹; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 ^- ⁹; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.

PubMed Disclaimer

Figures

**Figure 1.**
Manhattan plot and regional association plots. (A) Manhattan plot for all analyzed markers (the inset is for markers on the X chromosome); (**B,C**) regional association plots for the two novel risk loci (left: 9p21.3, right: *ERBB2* region).

**Figure 2.**
Genetic effect sizes for the novel risk loci. Forest plots displaying the odds ratios (OR) and 95% confidence intervals for the most significant SNPs in the (A) 9p21.3 region and (B) the *ERBB2* region. Horizontal lines indicate the 95% confidence interval of the OR for each study, with a shaded box around the point estimate, drawn proportional to the sample size. The diamond indicates the overall weighted OR for all samples included in the meta-analysis.

See this image and copyright information in PMC

References

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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Affiliations

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous