Genetic Risk Factor Suicidal Behavior

遗传风险因素自杀行为

• 批准号: 7628003
• 负责人: VIRGINIA L WILLOUR
• 金额: $ 29.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-11 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628003
• 关键词: 2p11; Accounting; Adoption; Aggressive behavior; Alcoholism; Alleles; Biological; Bipolar Disorder; Candidate Disease Gene; Cause of Death; Classification; Code; Collection; DNA; Exons; Family; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Goals; Haplotypes; Heritability; Impulsivity; Individual; Introns; Investigation; Literature; Major Depressive Disorder; Mental disorders; Molecular; Molecular Genetics; Mood Disorders; National Institute of Mental Health; Neurobiology; Neurons; Neurotransmitters; Nucleic Acid Regulatory Sequences; Pharmaceutical Preparations; Phenotype; Population Control; Predisposition; Principal Investigator; Proteins; Psychiatrist; Publishing; Recording of previous events; Research; Research Personnel; Risk; Sampling; Staging; Suicide; Suicide attempt; Susceptibility Gene; Testing; Twin Multiple Birth; United States; United States National Institutes of Health; Variant; Work; base; case control; density; design; disorder control; genetic pedigree; genetic risk factor; genetic variant; genome wide association study; high risk; life history; new therapeutic target; novel; positional cloning; sample collection; suicidal; suicidal behavior; trait

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.

描述（由申请人提供）：本申请由一位新的主要研究者提出，旨在鉴定赋予自杀行为易感性的新型基因变异。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易患精神疾病，但也有一个独立于精神疾病的遗传方面。这种独立性可能是攻击性和冲动性的一种倾向。自杀行为的遗传学研究主要集中在多巴胺能基因上，因为自杀受试者的神经生物学发现涉及这种神经递质。然而，很少有系统的自杀倾向的遗传学研究已经进行。只是在过去的两年里，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，另一个使用重度抑郁谱系，都发现了与2 p11 -12区域相关的证据。值得注意的是，当我们在双相情感障碍家系中检查自杀未遂表型时，我们发现基因组中最有力的连锁证据是在同一区域，在以前涉及的相同标记上。使用不同样本类型的三项研究结果的显著融合强烈表明在2 p11 -12区域存在倾向于自杀未遂的基因。我们建议直接测试这一假设，利用四个大的完善的遗传性情绪障碍样本收集，其中每一个都经历了仔细和严格的表型，并已进行了遗传研究，DNA样本可用。为此，我们组建了一个杰出的研究团队，其中包括分子和统计遗传学专家，自杀神经生物学的领导者，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的目标来实现我们的目标：1）在500例病例中从2 p11 -12候选区域中检测2772标签和编码SNP的基因型（有情绪障碍和自杀未遂史）和500名对照组，并进行相关证据测试; 2）在1000例病例和2000例对照的重复样本中，对特定目标1的前10%的SNPs进行基因分型，并以自杀未遂和终生攻击史作为表型进行关联研究;和3）基于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允许鉴定功能变体。发现易感基因和基因变异将允许识别自杀行为风险增加的人，影响高风险遗传变异个体自杀行为的药物，以及新的治疗靶点。