Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
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 Hou  1 Sarah E Bergen  2   3 Nirmala Akula  1 Jie Song  2 Christina M Hultman  2 Mikael Landén  4   2 Mazda Adli  5 Martin Alda  6 Raffaella Ardau  7 Bárbara Arias  8 Jean-Michel Aubry  9 Lena Backlund  10 Judith A Badner  11 Thomas B Barrett  12 Michael Bauer  13 Bernhard T Baune  14 Frank Bellivier  15 Antonio Benabarre  16 Susanne Bengesser  17 Wade H Berrettini  18 Abesh Kumar Bhattacharjee  19 Joanna M Biernacka  20   21 Armin Birner  17 Cinnamon S Bloss  22 Clara Brichant-Petitjean  15 Elise T Bui  1 William Byerley  23 Pablo Cervantes  24 Caterina Chillotti  7 Sven Cichon  25   26   27   28 Francesc Colom  16 William Coryell  29 David W Craig  30 Cristiana Cruceanu  31 Piotr M Czerski  32 Tony Davis  14 Alexandre Dayer  9 Franziska Degenhardt  25   26 Maria Del Zompo  33 J Raymond DePaulo  34 Howard J Edenberg  35 Bruno Étain  36 Peter Falkai  37 Tatiana Foroud  38 Andreas J Forstner  25   26 Louise Frisén  39   40 Mark A Frye  21 Janice M Fullerton  41   42 Sébastien Gard  43 Julie S Garnham  6 Elliot S Gershon  11 Fernando S Goes  34 Tiffany A Greenwood  19 Maria Grigoroiu-Serbanescu  44 Joanna Hauser  32 Urs Heilbronner  45   46 Stefanie Heilmann-Heimbach  25   26 Stefan Herms  25   26   28 Maria Hipolito  47 Shashi Hitturlingappa  14 Per Hoffmann  25   26   27   28 Andrea Hofmann  25   26 Stephane Jamain  36 Esther Jiménez  16 Jean-Pierre Kahn  48 Layla Kassem  1 John R Kelsoe  19 Sarah Kittel-Schneider  49 Sebastian Kliwicki  50 Daniel L Koller  38 Barbara König  51 Nina Lackner  17 Gonzalo Laje  1 Maren Lang  52 Catharina Lavebratt  10 William B Lawson  47 Marion Leboyer  36 Susan G Leckband  53 Chunyu Liu  54 Anna Maaser  25   26 Pamela B Mahon  34 Wolfgang Maier  55 Mario Maj  56 Mirko Manchia  33   57 Lina Martinsson  39 Michael J McCarthy  58 Susan L McElroy  59 Melvin G McInnis  60 Rebecca McKinney  19 Philip B Mitchell  61 Marina Mitjans  8 Francis M Mondimore  34 Palmiero Monteleone  56   62 Thomas W Mühleisen  25   26   27 Caroline M Nievergelt  19 Markus M Nöthen  25   26 Tomas Novák  63 John I Nurnberger Jr  64 Evaristus A Nwulia  47 Urban Ösby  65 Andrea Pfennig  13 James B Potash  66 Peter Propping  25 Andreas Reif  49 Eva Reininghaus  17 John Rice  67 Marcella Rietschel  52 Guy A Rouleau  68 Janusz K Rybakowski  50 Martin Schalling  10 William A Scheftner  69 Peter R Schofield  42   70 Nicholas J Schork  22 Thomas G Schulze  1   34   45   46   52 Johannes Schumacher  25   26 Barbara W Schweizer  34 Giovanni Severino  33 Tatyana Shekhtman  19 Paul D Shilling  19 Christian Simhandl  71 Claire M Slaney  6 Erin N Smith  22 Alessio Squassina  33 Thomas Stamm  5 Pavla Stopkova  63 Fabian Streit  52 Jana Strohmaier  52 Szabolcs Szelinger  30 Sarah K Tighe  66 Alfonso Tortorella  56 Gustavo Turecki  31 Eduard Vieta  16 Julia Volkert  49 Stephanie H Witt  52 Adam Wright  61 Peter P Zandi  72 Peng Zhang  60 Sebastian Zollner  60 Francis J McMahon  73
Affiliations
Free PMC article
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. .
Free PMC article

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.

Figures

Figure 1.
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.
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.

Similar articles

See all similar articles

Cited by 36 articles

  • Statistical methods for testing X chromosome variant associations: application to sex-specific characteristics of bipolar disorder.
    Jons WA, Colby CL, McElroy SL, Frye MA, Biernacka JM, Winham SJ. Jons WA, et al. Biol Sex Differ. 2019 Dec 9;10(1):57. doi: 10.1186/s13293-019-0272-4. Biol Sex Differ. 2019. PMID: 31818333 Free PMC article.
  • Usp9X Controls Ankyrin-Repeat Domain Protein Homeostasis during Dendritic Spine Development.
    Yoon S, Parnell E, Kasherman M, Forrest MP, Myczek K, Premarathne S, Sanchez Vega MC, Piper M, Burne THJ, Jolly LA, Wood SA, Penzes P. Yoon S, et al. Neuron. 2020 Feb 5;105(3):506-521.e7. doi: 10.1016/j.neuron.2019.11.003. Epub 2019 Dec 5. Neuron. 2020. PMID: 31813652
  • Coding and Non-Coding RNA Abnormalities in Bipolar Disorder.
    Luykx JJ, Giuliani F, Giuliani G, Veldink J. Luykx JJ, et al. Genes (Basel). 2019 Nov 19;10(11):946. doi: 10.3390/genes10110946. Genes (Basel). 2019. PMID: 31752442 Free PMC article.
  • Association of SYNE1 locus with bipolar disorder in Chinese population.
    Li W, Yang Y, Luo B, Zhang Y, Song X, Li M, Lv L. Li W, et al. Hereditas. 2019 Jun 17;156:19. doi: 10.1186/s41065-019-0095-7. eCollection 2019. Hereditas. 2019. PMID: 31236099 Free PMC article.
  • Genome-wide association study identifies 30 loci associated with bipolar disorder.
    Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, Mattheisen M, Wang Y, Coleman JRI, Gaspar HA, de Leeuw CA, Steinberg S, Pavlides JMW, Trzaskowski M, Byrne EM, Pers TH, Holmans PA, Richards AL, Abbott L, Agerbo E, Akil H, Albani D, Alliey-Rodriguez N, Als TD, Anjorin A, Antilla V, Awasthi S, Badner JA, Bækvad-Hansen M, Barchas JD, Bass N, Bauer M, Belliveau R, Bergen SE, Pedersen CB, Bøen E, Boks MP, Boocock J, Budde M, Bunney W, Burmeister M, Bybjerg-Grauholm J, Byerley W, Casas M, Cerrato F, Cervantes P, Chambert K, Charney AW, Chen D, Churchhouse C, Clarke TK, Coryell W, Craig DW, Cruceanu C, Curtis D, Czerski PM, Dale AM, de Jong S, Degenhardt F, Del-Favero J, DePaulo JR, Djurovic S, Dobbyn AL, Dumont A, Elvsåshagen T, Escott-Price V, Fan CC, Fischer SB, Flickinger M, Foroud TM, Forty L, Frank J, Fraser C, Freimer NB, Frisén L, Gade K, Gage D, Garnham J, Giambartolomei C, Pedersen MG, Goldstein J, Gordon SD, Gordon-Smith K, Green EK, Green MJ, Greenwood TA, Grove J, Guan W, Guzman-Parra J, Hamshere ML, Hautzinger M, Heilbronner U, Herms S, Hipolito M, Hoffmann P, Holland D, Huckins L, Jamain S, Johnson JS, Juréus A, Kandaswamy R, Karlsson R, Kennedy JL, Kittel-Schneider S, Knowles JA, Kogevinas M, Koller AC, Kupka R, Lavebratt C, Lawrence J, Lawson WB, Leber M, Lee PH, Levy SE, Li JZ, Liu C, Lucae S, Maaser A, MacIntyre DJ, Mahon PB, Maier W, Martinsson L, McCarroll S, McGuffin P, McInnis MG, McKay JD, Medeiros H, Medland SE, Meng F, Milani L, Montgomery GW, Morris DW, Mühleisen TW, Mullins N, Nguyen H, Nievergelt CM, Adolfsson AN, Nwulia EA, O'Donovan C, Loohuis LMO, Ori APS, Oruc L, Ösby U, Perlis RH, Perry A, Pfennig A, Potash JB, Purcell SM, Regeer EJ, Reif A, Reinbold CS, Rice JP, Rivas F, Rivera M, Roussos P, Ruderfer DM, Ryu E, Sánchez-Mora C, Schatzberg AF, Scheftner WA, Schork NJ, Shannon Weickert C, Shehktman T, Shilling PD, Sigurdsson E, Slaney C, Smeland OB, Sobell JL, Søholm Hansen C, Spijker AT, St Clair D, Steffens M, Strauss JS, Streit F, Strohmaier J, Szelinger S, Thompson RC, Thorgeirsson TE, Treutlein J, Vedder H, Wang W, Watson SJ, Weickert TW, Witt SH, Xi S, Xu W, Young AH, Zandi P, Zhang P, Zöllner S; eQTLGen Consortium; BIOS Consortium, Adolfsson R, Agartz I, Alda M, Backlund L, Baune BT, Bellivier F, Berrettini WH, Biernacka JM, Blackwood DHR, Boehnke M, Børglum AD, Corvin A, Craddock N, Daly MJ, Dannlowski U, Esko T, Etain B, Frye M, Fullerton JM, Gershon ES, Gill M, Goes F, Grigoroiu-Serbanescu M, Hauser J, Hougaard DM, Hultman CM, Jones I, Jones LA, Kahn RS, Kirov G, Landén M, Leboyer M, Lewis CM, Li QS, Lissowska J, Martin NG, Mayoral F, McElroy SL, McIntosh AM, McMahon FJ, Melle I, Metspalu A, Mitchell PB, Morken G, Mors O, Mortensen PB, Müller-Myhsok B, Myers RM, Neale BM, Nimgaonkar V, Nordentoft M, Nöthen MM, O'Donovan MC, Oedegaard KJ, Owen MJ, Paciga SA, Pato C, Pato MT, Posthuma D, Ramos-Quiroga JA, Ribasés M, Rietschel M, Rouleau GA, Schalling M, Schofield PR, Schulze TG, Serretti A, Smoller JW, Stefansson H, Stefansson K, Stordal E, Sullivan PF, Turecki G, Vaaler AE, Vieta E, Vincent JB, Werge T, Nurnberger JI, Wray NR, Di Florio A, Edenberg HJ, Cichon S, Ophoff RA, Scott LJ, Andreassen OA, Kelsoe J, Sklar P; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium. Stahl EA, et al. Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1. Nat Genet. 2019. PMID: 31043756 Free PMC article.
See all "Cited by" articles

Publication types

Feedback