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

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 S Gershon, Fernando S Goes, Tiffany A Greenwood, Maria Grigoroiu-Serbanescu, Joanna 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 R Schofield, Nicholas J Schork, Thomas G Schulze, Johannes Schumacher, Barbara W Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D Shilling, Christian Simhandl, Claire M 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

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.