Since 1988 the NIMH Genetics Initiative has supported a national resource for the study of bipolar disorder (BP). This extension of the national genetic resource includes a sample of over 2000 unrelated BP probands, over 1000 affected siblings, and available parents for case-control and family-based association studies. Control samples are obtained through the NIMH Genetics Initiative national resource. Probands and parents have been ascertained and assessed at eleven sites. This sample serves as a national resource for genome-wide association and many other studies. Using this sample, we carried out the first genome-wide genetic association study of bipolar disorder, using over 550,000 single nucleotide markers and cases drawn from this collection, as well as controls collected by the NIMH Genetics Initiative, along with a set of cases and controls collected by collaborators in Germany. This study, first published in early 2007, demonstrated that many genes of small effect contribute to the risk of bipolar disorder, including genes encoding diacyglyceral kinase eta (DGKH), and ankyrin 3 (ANK3), the latter of which was subsequently found to contribute to risk of bipolar disorder in several independent samples. A major related project, known as the Bipolar Disorder Phenome Project, aims to collate all of the clinical data collected from all 4000+ participants in the Genetics Initiative study that have been enrolled since 1992. This database was released to the scientific community in 2007. In 2008, we added an additional 1000+ individuals to the database, which has now been used by researchers around the world interested in the clinical phenotype of familial bipolar disorder and related conditions. In 2007, this sample was selected by the Genetic Association Information Network (GAIN) for genotyping using 1 million single nucleotide markers. The genotyping was completed in early 2008 and the data were released to the scientific community as a resource for genetic studies. Using these data, we and collaborators completed a 2nd generation genome-wide association study of BP in European-American and African-American subjects, which was published in early 2009. We also carried out a replication study of previously-reported associations with 2 markers in the gene encoding ankyrin 3 (ANK3), a protein involved in conduction of nerve impulses. We showed that 2 markers in this gene were independent risk factors for bipolar disorder. In the past year, we completed a meta-analysis of an additional 10000 cases and controls - the largest sample to date. We identified a locus on chromosome 3p that is associated with both bipolar and major depressive disorder and may represent an example of a shared risk locus. Among several genes in the region, we found that one, PBRM1, is also overexpressed in post-mortem brain from people with bipolar disorder. PBRM1 encodes polybromo1, which plays an important role in chromatin remodeling, a key mechanism of gene expression regulation. Ongoing work is aimed at additional meta-analyses of genome-wide data within the context of the Psychiatric GWAS Consortium, functional genomic studies of genes in the 3p risk locus, and related projects.
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