Genetic Risk Factor Suicidal Behavior

描述（由申请人提供）：该申请由一位新的首席研究员提出，旨在鉴定具有自杀行为易感性的新基因变异。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，但迪恩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，自杀行为有很大的遗传因素。虽然这种遗传性部分是由于对精神疾病的倾向，但也有独立于精神疾病的遗传方面。这种独立的特征可能会导致攻击性和冲动性。自杀行为的遗传研究主要集中在血清素能基因上，因为自杀受试者的神经生物学发现暗示了这种神经递质。然而，很少对自杀行为进行系统的基因调查。直到最近两年，人们才首次尝试检查与这种表型相关的全基因组。最早发表的两项研究，一项使用酗酒谱系，另一项使用重度抑郁症谱系，都发现了与2p11-12区域相关的证据。值得注意的是，当我们检查双相情感障碍谱系中企图自杀的表型时，我们发现基因组中最有力的联系证据是在同一区域，在先前涉及的相同标记上。这三个不同样本类型的研究结果的显著融合强烈表明，在2p11-12区域存在一种易导致自杀未遂的基因。我们建议通过使用四个大型的成熟的遗传情绪障碍样本集合来直接测试这一假设，每个样本都经过了仔细和严格的表型分析，并进行了遗传研究，并提供了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专家、自杀神经生物学的领军人物，以及在自杀表型方面具有专长的精神病学家。我们提出了三个具体的目标来实现我们的目标：1)在500例（有情绪障碍和自杀未遂史的）病例和500例对照中，对基因型2772标记和来自2p11-12候选区域的编码snp进行测试，并对关联证据进行测试；2)在1000例病例和2000例对照的复制样本中，对特异性目标1中前10%的snp进行基因型分析，并使用自杀未遂和终生攻击史作为表型进行关联研究；3)根据关联分析结果和功能考虑，选择3-5个候选基因进行测序，以便鉴定功能变异。发现易感基因和基因变异将有助于确定自杀行为风险增加的人群、影响高风险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.