Attempted Suicide Candidate Gene Resequencing

描述(由申请者提供)：本申请旨在鉴定与自杀行为易感性相关的新基因变异。虽然自杀可能是精神疾病最可怕的方面，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。虽然有证据表明，这种遗传性在一定程度上是由情绪障碍的易感性造成的，但其他证据表明，可能存在独立的可遗传方面，可能跨越多种精神障碍。这一独立特征被假设为易受攻击性和冲动的影响；由于自杀受试者的神经生物学发现涉及这种神经递质，因此对这一特征的遗传学研究主要集中在5-羟色胺能基因上。然而，很少对自杀表型进行系统的遗传学研究。只有在过去的六年里，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，一个使用酗酒家系，另一个使用主要的抑郁症家系，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家系集中的自杀行为表型时，我们发现跨基因组联系的最有力证据在相同的区域，在先前暗示的相同的标记上。在使用不同样本类型的三项全基因组研究中，这一令人印象深刻的发现汇聚在一起，有力地表明在2p11-12区域存在一种倾向于自杀行为的基因。我们在一项全基因组关联研究中直接验证了这一假设，方法是将双相情感障碍和自杀未遂(未遂者)患者的基因类型与双相情感障碍患者和没有自杀未遂史的患者(非自杀未遂者)的基因类型进行比较。这项分析鉴定了LRRTM4基因，它编码一种神经系统跨膜蛋白，触发兴奋性突触的形成，并定位于2p12。一项使用自杀未遂表型的独立病例对照关联研究也发现了LRRTM4基因。我们建议通过进行大规模的重新测序工作来跟进这些结果，旨在识别LRRTM4的风险等位基因目录，目的是识别增加自杀行为风险的遗传变异，从而为表型的遗传基础提供前所未有的洞察力。我们的项目将利用一支杰出的研究团队的多样化和互补性技能集，其中包括分子遗传学、统计遗传学、生物信息学和精神病理学的专家。找到影响自杀行为的基因变异，将有助于识别携带高危等位基因的人，并识别影响携带这些高危等位基因的个体自杀行为的药物。它还将为自杀行为的生物学基础提供新的见解，并提供新的治疗靶点。

DESCRIPTION (provided by applicant): This application aims to identify novel gene variants conferring susceptibility to suicidal behavior. While suicidality 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 been devoted to its biological basis. Yet family, twin, and adoption studies make clear that suicidal behavior has a substantial heritable component. While there is evidence that this heritability is accounted for in part by a liability to mood disorder, other evidence suggests an independent heritable facet that may cut across multiple psychiatric disorders. This independent feature has been hypothesized to be a liability to aggressiveness and impulsivity; the genetic study of this feature has focused on serotonergic genes because of neurobiological findings in suicidal subjects implicating this neurotransmitter. However, little systematic genetic investigation of the suicidality phenotype has been undertaken. Only in the last six 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 using major depression pedigrees, both found evidence of linkage to the 2p11-12 region. Remarkably, when we examined the suicidal behavior phenotype in our bipolar disorder pedigree set, we found that the strongest evidence for linkage across the genome was in the same region, at the same markers implicated previously. This impressive confluence of findings across three genome-wide studies using differing sample types strongly suggests the presence of a gene predisposing to suicidal behavior in the 2p11- 12 region. We tested this hypothesis directly in a genome-wide association study by comparing genotypes from subjects with bipolar disorder and a history of attempted suicide (attempters) to those from subjects with bipolar disorder and no history of attempted suicide (non-attempters). This analysis identified the LRRTM4 gene, which encodes a nervous system transmembrane protein that triggers formation of excitatory synapses and localizes to 2p12. An independent case-control association study using the attempted suicide phenotype also identified the LRRTM4 gene. We propose to follow-up these results by conducting a large-scale resequencing effort designed to identify a catalog of risk alleles for LRRTM4, with the goal of identifying genetic variation that increases the risk of suicidal behavior, thereby providing unprecedented insight into the genetic basis of the phenotype. Our project will make use of the diverse and complementary skill sets of an outstanding team of investigators that includes experts in molecular genetics, statistical genetics, bioinformatics, and psychopathology. Finding genetic variants that influence suicidal behavior would allow for the identification of people with high-risk alleles and the identification of medications that influence suicidal behavior in individuals with these high-risk alleles. It would also provide new insights into the biological basis of suicidal behavior and provide new therapeutic targets.