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Meta-Analysis
, 51 (5), 793-803

Genome-wide Association Study Identifies 30 Loci Associated With Bipolar Disorder

Eli A Stahl  1   2   3 Gerome Breen  4   5 Andreas J Forstner  6   7   8   9   10 Andrew McQuillin  11 Stephan Ripke  12   13   14 Vassily Trubetskoy  13 Manuel Mattheisen  15   16   17   18   19 Yunpeng Wang  20   21 Jonathan R I Coleman  4   5 Héléna A Gaspar  4   5 Christiaan A de Leeuw  22 Stacy Steinberg  23 Jennifer M Whitehead Pavlides  24 Maciej Trzaskowski  25 Enda M Byrne  25 Tune H Pers  26   27 Peter A Holmans  28 Alexander L Richards  28 Liam Abbott  12 Esben Agerbo  19   29 Huda Akil  30 Diego Albani  31 Ney Alliey-Rodriguez  32 Thomas D Als  15   16   19 Adebayo Anjorin  33 Verneri Antilla  14 Swapnil Awasthi  13 Judith A Badner  34 Marie Bækvad-Hansen  19   35 Jack D Barchas  36 Nicholas Bass  11 Michael Bauer  37 Richard Belliveau  12 Sarah E Bergen  38 Carsten Bøcker Pedersen  19   29 Erlend Bøen  39 Marco P Boks  40 James Boocock  41 Monika Budde  42 William Bunney  43 Margit Burmeister  44 Jonas Bybjerg-Grauholm  19   35 William Byerley  45 Miquel Casas  46   47   48   49 Felecia Cerrato  12 Pablo Cervantes  50 Kimberly Chambert  12 Alexander W Charney  51 Danfeng Chen  12 Claire Churchhouse  12   14 Toni-Kim Clarke  52 William Coryell  53 David W Craig  54 Cristiana Cruceanu  50   55 David Curtis  56   57 Piotr M Czerski  58 Anders M Dale  59   60   61   62 Simone de Jong  4   5 Franziska Degenhardt  8 Jurgen Del-Favero  63 J Raymond DePaulo  64 Srdjan Djurovic  65   66 Amanda L Dobbyn  67   51 Ashley Dumont  12 Torbjørn Elvsåshagen  68   69 Valentina Escott-Price  28 Chun Chieh Fan  62 Sascha B Fischer  6   10 Matthew Flickinger  70 Tatiana M Foroud  71 Liz Forty  28 Josef Frank  72 Christine Fraser  28 Nelson B Freimer  73 Louise Frisén  74   75   76 Katrin Gade  42   77 Diane Gage  12 Julie Garnham  78 Claudia Giambartolomei  79 Marianne Giørtz Pedersen  19   29 Jaqueline Goldstein  12 Scott D Gordon  80 Katherine Gordon-Smith  81 Elaine K Green  82 Melissa J Green  83   84 Tiffany A Greenwood  61 Jakob Grove  15   16   19   85 Weihua Guan  86 José Guzman-Parra  87 Marian L Hamshere  28 Martin Hautzinger  88 Urs Heilbronner  42 Stefan Herms  6   8   10 Maria Hipolito  89 Per Hoffmann  6   8   10 Dominic Holland  59   90 Laura Huckins  67   51 Stéphane Jamain  91   92 Jessica S Johnson  67   51 Anders Juréus  38 Radhika Kandaswamy  4 Robert Karlsson  38 James L Kennedy  93   94   95   96 Sarah Kittel-Schneider  97 James A Knowles  98   99 Manolis Kogevinas  100 Anna C Koller  8 Ralph Kupka  101   102   103 Catharina Lavebratt  74 Jacob Lawrence  104 William B Lawson  89 Markus Leber  105 Phil H Lee  12   14   106 Shawn E Levy  107 Jun Z Li  108 Chunyu Liu  109 Susanne Lucae  110 Anna Maaser  8 Donald J MacIntyre  111   112 Pamela B Mahon  64   113 Wolfgang Maier  114 Lina Martinsson  75 Steve McCarroll  12   115 Peter McGuffin  4 Melvin G McInnis  116 James D McKay  117 Helena Medeiros  99 Sarah E Medland  80 Fan Meng  30   116 Lili Milani  118 Grant W Montgomery  25 Derek W Morris  119   120 Thomas W Mühleisen  6   121 Niamh Mullins  4 Hoang Nguyen  67   51 Caroline M Nievergelt  61   122 Annelie Nordin Adolfsson  123 Evaristus A Nwulia  89 Claire O'Donovan  78 Loes M Olde Loohuis  73 Anil P S Ori  73 Lilijana Oruc  124 Urban Ösby  125 Roy H Perlis  126   127 Amy Perry  81 Andrea Pfennig  37 James B Potash  64 Shaun M Purcell  51   113 Eline J Regeer  128 Andreas Reif  97 Céline S Reinbold  6   10 John P Rice  129 Fabio Rivas  87 Margarita Rivera  4   130 Panos Roussos  67   51   131 Douglas M Ruderfer  132 Euijung Ryu  133 Cristina Sánchez-Mora  46   47   49 Alan F Schatzberg  134 William A Scheftner  135 Nicholas J Schork  136 Cynthia Shannon Weickert  83   84 Tatyana Shehktman  61 Paul D Shilling  61 Engilbert Sigurdsson  137 Claire Slaney  78 Olav B Smeland  138   139 Janet L Sobell  140 Christine Søholm Hansen  19   35 Anne T Spijker  141 David St Clair  142 Michael Steffens  143 John S Strauss  95   144 Fabian Streit  72 Jana Strohmaier  72 Szabolcs Szelinger  145 Robert C Thompson  116 Thorgeir E Thorgeirsson  23 Jens Treutlein  72 Helmut Vedder  146 Weiqing Wang  67   51 Stanley J Watson  116 Thomas W Weickert  83   84 Stephanie H Witt  72 Simon Xi  147 Wei Xu  148   149 Allan H Young  150 Peter Zandi  151 Peng Zhang  152 Sebastian Zöllner  116 eQTLGen ConsortiumBIOS ConsortiumRolf Adolfsson  123 Ingrid Agartz  17   39   153 Martin Alda  78   154 Lena Backlund  75 Bernhard T Baune  155   156 Frank Bellivier  157   158   159   160 Wade H Berrettini  161 Joanna M Biernacka  133 Douglas H R Blackwood  52 Michael Boehnke  70 Anders D Børglum  15   16   19 Aiden Corvin  120 Nicholas Craddock  28 Mark J Daly  12   14 Udo Dannlowski  156 Tõnu Esko  26   115   118   162 Bruno Etain  157   159   160   163 Mark Frye  164 Janice M Fullerton  84   165 Elliot S Gershon  32   166 Michael Gill  120 Fernando Goes  64 Maria Grigoroiu-Serbanescu  167 Joanna Hauser  58 David M Hougaard  19   35 Christina M Hultman  38 Ian Jones  28 Lisa A Jones  81 René S Kahn  51   40 George Kirov  28 Mikael Landén  38   168 Marion Leboyer  92   157   169 Cathryn M Lewis  4   5   170 Qingqin S Li  171 Jolanta Lissowska  172 Nicholas G Martin  80   173 Fermin Mayoral  87 Susan L McElroy  174 Andrew M McIntosh  52   175 Francis J McMahon  176 Ingrid Melle  177 Andres Metspalu  118   178 Philip B Mitchell  83 Gunnar Morken  179   180 Ole Mors  19   181 Preben Bo Mortensen  15   19   29 Bertram Müller-Myhsok  55   182   183 Richard M Myers  107 Benjamin M Neale  26   12   14 Vishwajit Nimgaonkar  184 Merete Nordentoft  19   185 Markus M Nöthen  8 Michael C O'Donovan  28 Ketil J Oedegaard  186   187 Michael J Owen  28 Sara A Paciga  188 Carlos Pato  99   189 Michele T Pato  99 Danielle Posthuma  22   190 Josep Antoni Ramos-Quiroga  46   47   48   49 Marta Ribasés  46   47   49 Marcella Rietschel  72 Guy A Rouleau  191   192 Martin Schalling  74 Peter R Schofield  84   165 Thomas G Schulze  42   64   72   77   176 Alessandro Serretti  193 Jordan W Smoller  12   194   106 Hreinn Stefansson  23 Kari Stefansson  23   137 Eystein Stordal  195   196 Patrick F Sullivan  38   197   198 Gustavo Turecki  199 Arne E Vaaler  200 Eduard Vieta  201 John B Vincent  144 Thomas Werge  19   202   203 John I Nurnberger  204 Naomi R Wray  24   25 Arianna Di Florio  28   198 Howard J Edenberg  205 Sven Cichon  6   8   10   121 Roel A Ophoff  40   41   73 Laura J Scott  70 Ole A Andreassen  138   139 John Kelsoe  206 Pamela Sklar  67   51   152 Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
Affiliations
Meta-Analysis

Genome-wide Association Study Identifies 30 Loci Associated With Bipolar Disorder

Eli A Stahl et al. Nat Genet.

Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

Conflict of interest statement

Competing Interest:

T.E. Thorgeirsson, S. Steinberg, H. Stefansson and K. Stefansson are employed by deCODE Genetics/Amgen. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H. Young has given paid lectures and is on advisory boards for the following companies with drugs used in affective and related disorders: Astra Zeneca, Eli Lilly, Janssen, Lundbeck, Sunovion, Servier, Livanova. A.H. Young is Lead Investigator for Embolden Study (Astra Zeneca), BCI Neuroplasticity study and Aripiprazole Mania Study, which are investigator-initiated studies from Astra Zeneca, Eli Lilly, Lundbeck, and Wyeth. J. Nurnberger is an investigator for Janssen. P.F. Sullivan reports the following potentially competing financial interests: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member), and Roche (grant recipient, speaker reimbursement). G. Breen reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. O.A. Andreassen has received speaker fees from Lundbeck. J.Antoni Ramos-Quiroga was on the speakers’ bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, and Eli- Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. Dr. E. Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020, and the Stanley Medical Research Institute. T. Elvsåshagen has received speaker fees from Lundbeck. All other authors declare no financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Manhattan plot for our primary genomewide association analysis of 20,352 cases and 31,358 controls. GWAS -log10P-values are plotted for all SNPs across chromosomes 1-22 (diamonds, green for loci with lead SNP GWAS P < 10−6). Combined GWAS+followup −log10P-values for lead SNPs reaching genome-wide significance in either GWAS or combined analysis (triangles, inverted if GWAS+followup −log10P > GWAS -log10P). Labels correspond to gene symbols previously reported for published loci (black) and the nearest genes for novel loci (blue), at top if GWAS+followup P < 5×10−8. Loci with one-tailed follow-up p > 0.05 (Table 1) have dotted underlined locus names.
Figure 2.
Figure 2.
Association of BD1 and BD2 subtypes with schizophrenia (SCZ) and major depression (DEPR) polygenic risk scores (PRS). Shown are mean PRS values (1 s.e. error bars), adjusted for study and ancestry covariates and scaled to the PRS mean and sd in control subjects, in BD1 (red) and BD2 (blue) cases, for increasing source GWAS P-value thresholds (increasing grey) as indicated. P-values (italics) test BD1 vs BD2 mean PRS, in logistic regression of case subtype on PRS with covariates. Results are detailed in Supplementary Table 13.

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