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Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.

Pamela Sklar 1, 2, * Stephan Ripke 2, 3 Laura Scott 4 Ole Andreassen 5, 6 Sven Cichon 7, 8, 9 Nick Craddock 10 Howard Edenberg 11 John Nurnberger 12, 13 Marcella Rietschel 14 Douglas Blackwood 15, 16 Aiden Corvin 17 Matthew Flickinger 4 Weihua Guan 4 Morten Mattingsdal 5, 18 Andrew Mcquillin 19 Phoenix Kwan 4 Thomas Wienker 20 Mark Daly 2, 3 Frank Dudbridge 21 Peter Holmans 10, 22 Danyu Lin 23 Margit Burmeister 24 Tiffany Greenwood 25 Marian Hamshere 10, 26 Pierandrea Muglia 26 Erin Smith 27 Peter Zandi 28 Caroline Nievergelt 25 Rebecca Mckinney 25 Paul Shilling 25 Nicholas Schork 29 Cinnamon Bloss 27 Tatiana Foroud 12 Daniel Koller 12 Elliot Gershon 30 Chunyu Liu 30 Judith Badner 30 William Scheftner 31 William Lawson 32 Evaristus Nwulia 32 Maria Hipolito 32 William Coryell 33 John Rice 34 William Byerley 35 Francis Mcmahon 36 Thomas Schulze 14, 36, 37 Wade Berrettini 38 Falk Lohoff 38 James Potash 28 Pamela Mahon 28 Melvin Mcinnis 39 Sebastian Zöllner 39 Peng Zhang 39 David Craig 40 Szabocls Szelinger 40 Thomas Barrett 41 René Breuer 14 Sandra Meier 14 Jana Strohmaier 14 Stephanie Witt 14 Federica Tozzi 26 Anne Farmer 42 Peter Mcguffin 42 John Strauss 43 Wei Xu 44 James Kennedy 45 John Vincent 43 Keith Matthews 46 Richard Day 47 Manuel Ferreira 2, 3, 48 Colm O'Dushlaine 2, 3 Roy Perlis 2, 3 Soumya Raychaudhuri 2, 3 Douglas Ruderfer 2, 3 Phil Hyoun 2 Jordan Smoller 3, 2 Jun Li 24 Devin Absher 49 Robert Thompson 50 Fan Guo Meng 51 Alan Schatzberg 52 William Bunney 50 Jack Barchas 51 Edward Jones 53 Stanley Watson 54 Richard Myers 49 Huda Akil 54 Michael Boehnke 4 Kim Chambert 3 Jennifer Moran 3 Ed Scolnick 3 Srdjan Djurovic 5, 55 Ingrid Melle 5, 6 Gunnar Morken 56, 57 Michael Gill 10, 17 Derek Morris 17 Emma Quinn 1, 17 Thomas Mühleisen 7, 8 Franziska Degenhardt 7, 8 Manuel Mattheisen 20, 8 Johannes Schumacher 8 Wolfgang Maier 58 Michael Steffens 20 Peter Propping 8 Markus Nöthen 7, 8 Adebayo Anjorin 19 Nick Bass 19 Hugh Gurling 19 Radhika Kandaswamy 19 Jacob Lawrence 19 Kevin Mcghee 15, 16 Andrew Mcintosh 15, 16 Alan Mclean 15, 16 Walter Muir 15, 16 Benjamin Pickard 15, 16 Gerome Breen 42, 59 David St Clair 59 Sian Caesar 60 Katherine Gordon-Smith 10, 60 Lisa Jones 60 Christine Fraser 10 Elaine Green 10 Detelina Grozeva 10 Ian Jones 10 George Kirov 10 Valentina Moskvina 10, 26 Ivan Nikolov 1, 10 Michael O'Donovan 1, 10 Michael Owen 10 David Collier 42 Amanda Elkin 42 Richard Williamson 42 Allan Young 46, 61 I Nicol Ferrier 46 Kari Stefansson 62 Hreinn Stefansson 62 Porgeir Porgeirsson 62 Stacy Steinberg 62 Omar Gustafsson 62 Sarah Bergen 2, 3 Vishwajit Nimgaonkar 63 Christina Hultman 64 Mikael Landén 64, 65 Paul Lichtenstein 64 Patrick Sullivan 66 Martin Schalling 67 Urban Osby 67 Lena Backlund 68 Louise Frisén 67 Niklas Langstrom 65 Stéphane Jamain 69, 70, 71 Marion Leboyer 69, 70, 71 Bruno Etain 69, 70, 71 Frank Bellivier 69, 70, 71 Hannes Petursson 72 Engilbert Sigur Sson 72 Bertram Müller-Mysok 73 Susanne Lucae 73 Markus Schwarz 74 Peter Schofield 75, 76 Nick Martin 48 Grant Montgomery 48 Mark Lathrop 77 Högni Oskarsson 78 Michael Bauer 79 Adam Wright 80 Philip Mitchell 80 Martin Hautzinger 81 Andreas Reif 82 John Kelsoe 25, 83 Shaun Purcell 3, 2
* Corresponding author
1 Division of Psychiatric Genomics
2 Center for Human Genetic Research
3 Stanley Center for Psychiatric Research
4 Department of Biostatistics and Center for Statistical Genetics
5 Institute of Clinical Medicine [Oslo]
6 Division of Mental Health and Addiction
7 Department of Genomics, Life and Brain Center
8 Institute of Human Genetics
9 INM-1 - Institute of Neuroscience and Medicine
10 MRC Centre for Neuropsychiatric Genetics and Genomics
11 Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics
12 Department of Psychiatry
13 Department of Medical and Molecular Genetics
14 Department of Genetic Epidemiology in Psychiatry [Mannhein]
15 Division of Psychiatry
16 Medical Genetics Section
17 Neuropsychiatric Genetics Research Group
18 Sorlandet Hospital HF
19 Department of Psychiatry and Behavioral Sciences
20 Department of Biomedicine and the Centre for Integrative Sequencing
21 LSHTM - London School of Hygiene and Tropical Medicine
22 Biostatistics and Bioinformatics Unit
23 Department of Biostatistics
24 Department of Human Genetics, Department of Psychiatry
25 Department of Psychiatry
26 Neurosciences Centre of Excellence in Drug Discovery
27 The Scripps Translational Science Institute and Scripps Health
28 Department of Mental Health
29 The Scripps Translational Science Institute and The Scripps Research Institute
30 McKusick-Nathans Institute of Genetic Medicine
31 Rush University Medical Center [Chicago]
32 Department of Psychiatry and Behavioral Sciences
33 Department of Psychiatry
34 Washington University School of Medicine
35 Department of Psychiatry
36 Unit on the Genetic Basis of Mood and Anxiety Disorders
37 Department of Psychiatry and Psychotherapy
38 Department of Psychiatry [Philadelphia]
39 Department of Psychiatry
40 TGen - The Translational Genomics Research Institute
41 Internal Medicine
42 SGDP - Social, Genetic and Developmental Psychiatry Centre
43 Molecular Neuropsychiatry and Development Laboratory
44 Department of Biostatistics
45 Psychiatric Neurogenetics Section
46 University of Dundee School of Medicine
47 School of Neurology, Neurobiology and Psychiatry
48 Queensland Institute of Medical Research
49 HudsonAlpha Institute for Biotechnology
50 Department of Psychiatry and Human Behavior
51 Department of Psychiatry
52 Department of Psychiatry and Behavioral Sciences [Stanford]
53 Department of Psychiatry and Behavioral Sciences
54 Molecular Psychiatry Laboratory
55 Deparment of Medical Genetics
56 Department of Psychiatry
57 Department of Neuroscience
58 Department of Psychiatry and Psychotherapy
59 Institute of Medical Sciences
60 Department of Psychiatry, School of Clinical and Experimental Medicine
61 Institute of Mental Health
62 deCODE Genetics
63 Department of Human Genetics
64 MEB - Department of Medical Epidemiology and Biostatistics
65 Insitute of Neuroscience and Physiology
66 Medstar Research Institute
67 Department of Molecular Medicine
68 Department of Psychiatry
69 IMRB - Institut Mondor de Recherche Biomédicale
70 Service de psychiatrie
71 ENBREC - European Network of Bipolar Research Expert Centres
72 Division of Psychiatry
73 Max Planck Institute of Psychiatry
74 Psychiatric Center Nordbaden
75 Prince of Wales Medical Research Institute
76 UNSW - University of New South Wales [Sydney]
77 CNG - Centre National de Génotypage
78 Therapeia
79 Department of Psychiatry and Psychotherapy, ENBREC Group
80 School of Psychiatry
81 Department of Clinical and Developmental Psychology
82 Department of Psychiatry
83 Department of Psychiatry, Special Treatment and Evaluation Program (STEP)
Abstract : We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.
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Pamela Sklar, Stephan Ripke, Laura Scott, Ole Andreassen, Sven Cichon, et al.. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.. Nature Genetics, Nature Publishing Group, 2011, 43 (10), pp.977-83. ⟨10.1038/ng.943⟩. ⟨inserm-00634944⟩

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