This application, by a new principal investigator, aims to identify novel gene variants conferring susceptibility to suicidal behavior. While suicidal behavior is perhaps the most dreaded aspect of psychiatric disorders, and among the leading causes of death among young people in the United States, relatively little research has Deen devoted to its biological basis. Yet family, twin, and adoption studies make clear that suicidal behavior has a substantial heritable component. Though this heritability is accounted for in part by a liability to psychiatric disorders, there is also a heritable facet independent of psychiatric disorders. This independent feature may be a liability to aggressiveness and impulsivity. The genetic study of suicidal behavior has focused on serotonergic genes because of neurobiological findings in suicidal subjects implicating this neurotransmitter. However, little systematic genetic investigation of suicidality has been undertaken. Only in the last two years have the first attempts been made to examine the whole genome for linkage with this phenotype. The first two published studies of this kind, one using alcoholism pedigrees and the other major depression pedigrees, both found evidence of linkage to the 2p11-12 region. Remarkably, when we examined the attempted suicide phenotype in our bipolar disorder pedigrees, we found that the strongest evidence for linkage in the genome was in the same region, at the same markers implicated previously. This remarkable confluence of findings across three studies using differing sample types strongly suggests the presence of a gene predisposing to attempted suicide in the 2p11-12 region. We propose to directly test this hypothesis by making use of four large well-established genetic mood disorder sample collections, each of which has undergone careful and rigorous phenotyping, and has been studied genetically, with DNA samples available. Towards this end, we have assembled an outstanding team of investigators that includes experts in molecular and statistical genetics, a leader in the neurobiology of suicide, and psychiatrists with expertise in the suicidality phenotype. We propose three specific aims to accomplish our goals: 1) genotype 2772 tag and coding SNPs from the 2p11-12 candidate region in 500 cases (with a mood disorder and a history of attempted suicide) and 500 controls and test for evidence of association;2) genotype the top 10 percent of SNPs from specific aim 1 in a replication sample of 1000 cases and 2000 controls and conduct an association study using both attempted suicide and lifetime history of aggression as the phenotypes;and 3) based on the results of the association analyses and on functional considerations, select 3-5 candidate genes for sequencing to allow for identification of functional variants. Finding susceptibility genes and gene variants would allow for the identification of people at increased risk for suicidal behavior, of medications that influence suicidal behavior in individuals with the high-risk genetic variants, and of new therapeutic targets.
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