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Genome-wide Studies Identify 11 New Genetic Links to Schizophrenia and Bipolar Disorder
Genome-wide association studies (GWAS), begun in 2005 as a coordinated international effort to search for genes associated with susceptibility for complex diseases, have yielded important findings in virtually every major medical field from cardiology to oncology to infectious diseases. The Psychiatric Genome-Wide Association Study Consortium, formed in 2007, is the world’s largest consortium in psychiatry, in which more than 250 researchers from over 20 countries participate and share genetic data from tens of thousands of patients. U.S. supporters of funding for the consortium are the National Institute for Mental Health and the Brain & Behavior Research Foundation, which has provided seed money for a number of projects.
Among Psychiatric GWAS Consortium projects recently reported, NARSAD Grantees Pablo Gejman, M.D., and Pamela Sklar, M.D., Ph.D., collaborated inconcurrent large-scale, international studies that have provided new evidence of genetic variations associated with increased risk for schizophrenia and for bipolar disorder. The research, published in the Sept. 18 issue of the journal Nature Genetics, also found that some of these variations contribute to both diseases.
The genome is the complete genetic package carried by each individual. Slight variations, or mutations, in DNA from individual to individual are called single nucleotide polymorphisms, or SNPs (pronounced “snips”). (Nucleotides are the molecular units of DNA.) Unlike illnesses that may be caused by a single genetic mutation, or a small number of mutations, neuroscientists now believe that small inputs from many genetic variants – and different ones in different individuals – may be at work in mental illnesses, including schizophrenia and bipolar disorder. As a consequence, identification of the sites of DNA variants associated with specific mental illnesses requires screening and comparing very large numbers of SNPs from large numbers of people, the need that led to the establishment of the Psychiatric GWAS Consortium.
Dr. Gejman, a NARSAD Distinguished Investigator Grantee in 2000, is director of the Center for Genetics in Psychiatry at the NorthShore University Health System and professor of psychiatry at the University of Chicago. In the GWAS study, he and his colleagues evaluated DNA sites, or loci, in more than 17,836 people with schizophrenia and 33,859 controls. The research yielded associations with schizophrenia for seven loci, five of them newly found. A joint analysis with a bipolar disorder sample identified three loci associated with both disorders.
Pamela Sklar, M.D., Ph.D.
The strongest new finding by the Gejman team was an association with a gene, MIR137 that is a known regulator of neuronal development, and four other loci that contain predicted targets of MIR137 activity. The authors note: “The association near MIR137, associations in multiple predicted MIR137 targets, and the known role of MIR137I in neuronal maturation and function together suggest an intriguing new insight into the pathogenesis of schizophrenia.”
Dr. Sklar, a 1995 and 1998 NARSAD Young Investigator Grantee, is chief of the Division of Psychiatric Genomics and professor of psychiatry, neuroscience and genetics and genomic sciences at the Mount Sinai School of Medicine, and NARSAD Young Investigator Grantee. The lead author of the bipolar study, she and her colleagues used data from 7,481 people with bipolar disorder and 9,250 healthy controls to examine millions of DNA loci in the largest GWAS study of bipolar disorder to date. They identified one new bipolar disorder susceptibility locus, but expressed the belief that increasing the sample sizes will confirm many additional loci.
“As is typical in studies of complex genetic disorders,” the authors noted, “our findings explain only a small fraction of bipolar disorder heritability.” They added that these findings “are consistent with many common susceptibility variants of relatively weak effect potentially operating together with rarer variants.”
Dennis S. Charney, M.D., a member of the Brain & Behavior Research Foundation Scientific Council, in commenting on the two studies, stated: “This research represents a significant step forward in understanding the genetic risk factors behind mental illness, paving the way for a new era in psychiatry.” Dr. Charney is Anne and Joel Ehrenkranz Dean of the Mount Sinai School of Medicine and executive vice president for academic affairs of the Mount Sinai Medical Center.
Drs. Gejman and Sklar and NARSAD Distinguished Investigator Grantee Patrick Sullivan, M.D., of the University of North Carolina, Chapel Hill, are members of the Psychiatric GWAS Consortium’s Coordinating Committee.