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

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

2016-01-01

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Abstract

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.