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

All 142 authors (show less):
Liping Hou, Sarah E. Bergen, Jie Song, Nirmala Akula, Christina M. Hultman, Mikael Landen, Mazda Adli, Jean-Michel Aubry, Martin Alda, Lena Backlund, Judith A. Badner, Raffaella Ardau, Thomas B. Barrett, Barbara Arias, Michael Bauer, Bernhard T. Baune, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Wade H. Berrettini, Abesh Kumar Bhattacharjee, Bruno Étain, 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 Etain, Markus M. Nothen, Urban Ösby, Peter Falkai, Tatiana Foroud, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Markus M. Nöthen, Janice M. Fullerton, Philip B. Mitchell, Sebastien Gard, Andrea Pfennig, Marina Mitjans, Julie S. Garnham, James B. Potash, Elliot S. Gershon, Peter Propping, Francis M. Mondimore, Fernando S. Goes, Andreas Reif, Tiffany A. Greenwood, Urban Osby, Eva Reininghaus, Maria Grigoroiu-Serbanescu, Palmiero Monteleone, Joanna Hauser, John Rice, Thomas W. Muhleisen, Urs Heilbronner, Stefanie Heilmann-Heimbach, Marcella Rietschel, Stefan Herms, Caroline M. Nievergelt, Maria Hipolito, Guy A. Rouleau, Shashi Hitturlingappa, Per Hoffmann, Janusz K. Rybakowski, Andrea Hofmann, Martin Schalling, Tomas Novak, Stephane Jamain, Esther Jimenez, William A. Scheftner, Jean-Pierre Kahn, John I. Nurnberger, Jana Strohmaier, Peter R. Schofield, Layla Kassem, John R. Kelsoe, Szabolcs Szelinger, Nicholas J. Schork, Sarah Kittel-Schneider, Sebastian Kliwicki, Evaristus A. Nwulia, Daniel L. Koller, Sarah K. Tighe, Thomas G. Schulze, Barbara Konig, Nina Lackner, Alfonso Tortorella, Johannes Schumacher, Gonzalo Laje, Maren Lang, Gustavo Turecki, Catharina Lavebratt, Barbara W. Schweizer, William B. Lawson, Marion Leboyer, Eduard Vieta, Giovanni Severino, Susan G. Leckband, Chunyu Liu, Julia Volkert, Anna Maaser, Mario Maj, Tatyana Shekhtman, Pamela B. Mahon, Stephanie H. Witt, Wolfgang Maier, Paul D. Shilling, Mirko Manchia, Christian Simhandl, Adam Wright, Lina Martinsson, Michael J. McCarthy, Peter P. Zandi, Claire M. Slaney, Susan L. McElroy, Melvin G. McInnis, Erin N. Smith, Rebecca McKinney, Peng Zhang, Alessio Squassina, Sebastian Zollner, Thomas Stamm, Pavla Stopkova, Fabian StreitORCID, Francis J. McMahonORCID

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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.