Attempted Suicide Candidate Gene Resequencing

自杀未遂候选者基因重测序

• 批准号: 8267007
• 负责人: VIRGINIA L WILLOUR
• 金额: $ 19.62万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-12 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267007
• 关键词: 2p11; 2p12; Accounting; Adoption; Alcoholism; Alleles; Bioinformatics; Biological; Bipolar Disorder; Candidate Disease Gene; Cataloging; Catalogs; Cause of Death; DNA Resequencing; Data; Excitatory Synapse; Exons; Family; Female; Funding; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Heritability; Impulsivity; Individual; Integral Membrane Protein; Introns; Investigation; Logistic Regressions; Major Depressive Disorder; Mental disorders; Molecular Genetics; Mood Disorders; Nervous system structure; Neurobiology; Neurotransmitters; Nucleic Acid Regulatory Sequences; Pharmaceutical Preparations; Phenotype; Predisposition; Psychopathology; Publishing; Recording of previous events; Research; Research Personnel; Risk; Sampling; Suicide; Suicide attempt; Susceptibility Gene; Testing; Time; Twin Multiple Birth; United States; Variant; Work; base; case control; design; follow-up; genetic pedigree; genetic variant; genome wide association study; high risk; in vivo Model; insight; new therapeutic target; novel; promoter; skills; suicidal; suicidal behavior; suicide attempter; therapeutic target

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.

描述（由申请人提供）：本申请旨在鉴定赋予自杀行为易感性的新型基因变体。虽然自杀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，自杀行为有很大的遗传因素。虽然有证据表明，这种遗传性部分是由情绪障碍的倾向，其他证据表明，一个独立的遗传方面，可能跨越多种精神疾病。这种独立的特征被假设为易受攻击性和冲动性的影响;由于自杀受试者的神经生物学发现涉及这种神经递质，因此对这种特征的遗传学研究集中在多巴胺能基因上。然而，很少有系统的遗传研究自杀倾向的表型已经进行。只是在过去的六年里，人们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，一个使用酗酒谱系，另一个使用重性抑郁谱系，都发现了与2 p11 -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中的自杀行为表型时，我们发现跨基因组连锁的最强有力证据是在同一区域，在先前涉及的相同标记处。使用不同样本类型的三项全基因组研究的结果令人印象深刻，这强烈表明在2 p11 - 12区域存在自杀行为易感基因。我们在一项全基因组关联研究中直接检验了这一假设，方法是将有自杀未遂史的双相情感障碍受试者（自杀者）与无自杀未遂史的双相情感障碍受试者（非自杀者）的基因型进行比较。这项分析确定了LRRTM 4基因，该基因编码神经系统跨膜蛋白，触发兴奋性突触的形成并定位于2 p12。一项使用自杀未遂表型的独立病例对照关联研究也鉴定了LRRTM 4基因。我们建议通过进行大规模的重测序工作来跟踪这些结果，旨在确定LRRTM 4的风险等位基因目录，目的是确定增加自杀行为风险的遗传变异，从而提供前所未有的洞察力表型的遗传基础。我们的项目将利用一个优秀的研究团队的多样化和互补的技能，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。发现影响自杀行为的遗传变异将允许识别具有高风险等位基因的人，并识别影响具有这些高风险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。