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

By Liping Hou, Sarah E Bergen, Nirmala Akula, Jie Song, Christina M Hultman, Mikael Landén, Mazda Adli, Martin Alda, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Judith A Badner, Thomas B Barrett, Michael Bauer, Bernhard T Baune, Frank BELLIVIER, Antonio Benabarre, Susanne Bengesser, Wade H Berrettini, Abesh Kumar Bhattacharjee, Joanna M. Biernacka, Armin Birner, Cinnamon S Bloss, Clara Brichant-Petitjean, Elise T Bui, William Byerley, Pablo Cervantes, Caterina Chillotti, Sven Cichon, Francesc Colom, William Coryell, David W Craig, Cristiana Cruceanu, Piotr M. Czerski, Tony Davis, Alexandre Dayer, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Howard J. Edenberg, Bruno Étain, Peter Falkai, Tatiana Foroud, Andreas J. Forstner, Louise Frisén, Mark A Frye, Janice M. Fullerton, Sébastien Gard, Julie S Garnham, Elliot Gershon, Fernando S Goes, Tiffany A Greenwood, Maria Grigoroiu-Serbanescu, Joanna Twarowska-Hauser, Urs Heilbronner, Stefanie Heilmann-Heimbach, Stefan Herms, Maria Hipolito, Shashi Hitturlingappa, Per Hoffmann, Andrea Hofmann, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, John R Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Daniel L Koller, Barbara König, Nina Lackner, Gonzalo Laje, Maren Lang, Catharina Lavebratt, William B Lawson, Marion Leboyer, Susan G Leckband, Chunyu Liu, Anna Maaser, Pamela B Mahon, Wolfgang Maier, Mario Maj, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan L McElroy, Melvin G McInnis, Rebecca McKinney, Philip B. Mitchell, Marina Mitjans, Francis M Mondimore, Palmiero Monteleone, Thomas W. Mühleisen, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, John I. Nurnberger, Evaristus A Nwulia, Urban Ösby, Andrea Pfennig, James B. Potash, Peter Propping, Andreas Reif, Eva Reininghaus, John Rice, Marcella Rietschel, Guy A. Rouleau, Janusz K Rybakowski, Martin Schalling, William A Scheftner, Peter Schofield, Ali Torkamani, Thomas G Schulze, Johannes Schumacher, Barbara W Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D Shilling, Christian Simhandl, Claire Slaney, Erin N Smith, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Sarah K Tighe, Alfonso Tortorella, Gustavo Turecki, Eduard Vieta, Julia Volkert, Stephanie H. Witt, Adam Wright, Peter P Zandi, Peng Zhang, Sebastian Zollner, Francis J. McMahon

Posted 22 Mar 2016
bioRxiv DOI: 10.1101/044412 (published DOI: 10.1093/hmg/ddw181)

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. 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 = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 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.

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