Genetic Risk Factor Suicidal Behavior

描述(由申请人提供)：这项申请由一位新的首席研究员提出，旨在识别与自杀行为易感性相关的新基因变异。虽然自杀行为可能是精神疾病中最可怕的方面，也是美国年轻人死亡的主要原因之一，但对其生物学基础的研究相对较少。然而，家庭、双胞胎和收养研究表明，自杀行为有很大的可遗传成分。虽然这种遗传性在一定程度上是由精神障碍的易感性造成的，但也有一个独立于精神障碍的可遗传方面。这种独立的特征可能是攻击性和冲动的倾向。自杀行为的遗传学研究一直集中在5-羟色胺能基因上，因为自杀受试者的神经生物学发现与这种神经递质有关。然而，很少有人对自杀进行系统的遗传学研究。只是在最近两年，才首次尝试检查整个基因组与这种表型的联系。前两个发表的这类研究，一个使用酒精中毒家系，另一个主要的抑郁症家系，都发现了与2p11-12区域相关联的证据。值得注意的是，当我们检查双相情感障碍家系中的自杀未遂表型时，我们发现基因组中关联的最强证据在相同的区域，在先前暗示的相同的标记上。在使用不同样本类型的三项研究中，这一惊人的结果汇聚在一起，有力地表明在2p11-12区域存在一种易导致自杀未遂的基因。我们建议通过利用四个大型成熟的遗传性心境障碍样本收集来直接检验这一假设，每个样本都经过了仔细和严格的表型鉴定，并已进行了遗传学研究，提供了DNA样本。为此，我们组建了一支杰出的研究团队，其中包括分子和统计遗传学方面的专家，自杀神经生物学方面的领先者，以及在自杀表型方面具有专业知识的精神病学家。我们提出了三个具体目标来实现我们的目标：1)在500例患者(有情绪障碍和自杀未遂病史)和500名对照中，对2p11-12候选区域的2772标签和编码SNPs进行基因分型，并测试关联证据；2)在1000例患者和2000名对照的重复样本中，对来自特定目标1的前10%的SNPs进行基因分型，并以自杀未遂和终生攻击史为表型进行关联研究；以及3)根据关联分析的结果和功能考虑，选择3-5个候选基因进行测序，以便能够识别功能变异。发现易感基因和基因变异将有助于识别自杀行为风险增加的人，识别影响高危基因变异个体自杀行为的药物，以及新的治疗靶点。

DESCRIPTION (provided by applicant): 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.