Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4

• Published in: Nature genetics Vol. 43; no. 10; pp. 977 - 983
• Main Authors: Sklar, Pamela, Ripke, Stephan, Scott, Laura J, Andreassen, Ole A, Cichon, Sven, Craddock, Nick, Edenberg, Howard J, Nurnberger, John I, Rietschel, Marcella, Blackwood, Douglas, Corvin, Aiden, Flickinger, Matthew, Guan, Weihua, Mattingsdal, Morten, McQuillin, Andrew, Kwan, Phoenix, Wienker, Thomas F, Daly, Mark, Dudbridge, Frank, Holmans, Peter A, Lin, Danyu, Burmeister, Margit, Greenwood, Tiffany A, Hamshere, Marian L, Muglia, Pierandrea, Smith, Erin N, Zandi, Peter P, Nievergelt, Caroline M, McKinney, Rebecca, Shilling, Paul D, Schork, Nicholas J, Bloss, Cinnamon S, Foroud, Tatiana, Koller, Daniel L, Gershon, Elliot S, Liu, Chunyu, Badner, Judith A, Scheftner, William A, Lawson, William B, Nwulia, Evaristus A, Hipolito, Maria, Coryell, William, Rice, John, Byerley, William, McMahon, Francis J, Schulze, Thomas G, Berrettini, Wade, Lohoff, Falk W, Potash, James B, Mahon, Pamela B, McInnis, Melvin G, Zöllner, Sebastian, Zhang, Peng, Craig, David W, Szelinger, Szabocls, Barrett, Thomas B, Breuer, René, Meier, Sandra, Strohmaier, Jana, Witt, Stephanie H, Tozzi, Federica, Farmer, Anne, McGuffin, Peter, Strauss, John, Xu, Wei, Kennedy, James L, Vincent, John B, Matthews, Keith, Day, Richard, Ferreira, Manuel A, O'Dushlaine, Colm, Perlis, Roy, Raychaudhuri, Soumya, Ruderfer, Douglas, Lee, Phil H, Smoller, Jordan W, Li, Jun, Absher, Devin, Bunney, William E, Barchas, Jack D, Schatzberg, Alan F, Jones, Edward G, Meng, Fan, Thompson, Robert C, Watson, Stanley J, Myers, Richard M, Akil, Huda, Boehnke, Michael, Chambert, Kim, Moran, Jennifer, Scolnick, Ed, Djurovic, Srdjan, Melle, Ingrid, Morken, Gunnar, Gill, Michael, Morris, Derek, Quinn, Emma, Mühleisen, Thomas W, Degenhardt, Franziska A, Mattheisen, Manuel
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2011; Nature Publishing Group; Nature Pub. Co
• Subjects: 631/208/205/2138; 631/208/727/2000; 692/699/476/1333; Adult and adolescent clinical studies; Agriculture; Alleles; Animal Genetics and Genomics; Biochemistry, Molecular Biology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bipolar Disorder; Bipolar Disorder - genetics; Bipolar disorders; Calcium channels; Calcium Channels, L-Type; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Cancer Research; Case-Control Studies; Databases, Genetic; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic Loci; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genome-Wide Association Study; Genomes; Hospitals; Human Genetics; Humans; Independent sample; letter; Life Sciences; Linkage Disequilibrium; Medical sciences; Mental disorders; Mood disorders; Nuclear Proteins; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Polymorphism, Single Nucleotide; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psykiatri; Schizophrenia; Schizophrenia - genetics; Studies; Mood disorder; Bipolar disorder; Sensitivity; Identification; Association; Susceptibility locus
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.943

The Psychiatric GWAS Consortium Bipolar Disorder Working Group reports a large-scale genome-wide association study of 7,481 individuals with bipolar disorder with replication in 4,493 cases. The Consortium identifies a new susceptibility locus near ODZ4 and replicates a known association near CACNA1C for bipolar disorder. We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect ( P = 3.8 × 10 −7 ). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4 . Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.