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. Over the past year, we have carried out several large studies. We 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 BP (Schulze et al 2009). Ongoing work with collaborators at Johns Hopkins, Harvard, and the University of Cardiff is aimed at finding genes that play a role in shaping the clinical picture of bipolar disorder and response to treatment. We are testing the idea that subtypes of bipolar disorder, defined by differing clinical features, will prove to be a more tractable target for genetic association studies, producing larger effects that can be more easily replicated in independent samples. Key clinical features in this project include polarity at onset, frequency of manic and depressive episodes, and global functioning. We are also exploring variables that might be used to estimate an individual's response to lithium, one of the most effective current treatments for bipolar disorder. We have organized a large international collaboration, known as the Consortium on Lithium Genetics (ConLiGen), which aims to characterize lithium response in a large group of patients using reliable instruments, then perform a genome-wide association study. So far we have collected data and DNA from over 1000 cases.
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