Suicidal Behavior in Mood Disorders: Genes and Intermediate Phenotypes

描述(由申请人提供)：这项合作的R01涉及三个地点：美国纽约市的纽约州精神病研究所/精神卫生研究基金会(Mann)、加拿大蒙特利尔的麦吉尔大学(Turecki)和德国慕尼黑大学(Rujescu)，以研究自杀行为的复杂遗传基础。我们对最初的观察做出了贡献，表明自杀和非致命自杀企图具有不同于自杀背后的重大精神障碍的生物变化，如严重抑郁障碍或双相情感障碍。我们已经报道了与情绪障碍或自杀企图独立相关的候选基因关联。我们相信，该领域已经准备好进行一项重大的基因组调查，以寻找与自杀行为相关的基因，这些基因独立于主要的精神疾病。我们开发并测试了自杀行为的潜在预测压力-素质模型，该模型源于对危险因素的全面评估。抑郁的人有明显的(1)悲观情绪和(2)生活中攻击性/冲动的严重性，自杀行为的风险更大，其影响是累加的。这些临床表型成分可以在患者和自杀者身上进行现场测量。我们现在建议使用全基因组筛查来识别候选基因和这些基因中保守的单倍型块4000例，与精神匹配的对照组和健康志愿者相比，这些基因跨越了自杀行为的更高严重程度范围，即完全自杀和自杀未遂。我们有关于Axis I和Axis II诊断的数据，以及关于终生攻击性分数和当前抑郁症严重程度的数据，以便评估这些潜在的病因和潜在的行为内表型。我们有关于儿童期报告的身体或性虐待史的数据，这将是探索性基因-早期环境交互作用分析的重点。通过对最有希望的基因片段进行测序，将进一步确定因果SNPs。公共卫生相关性：自杀行为的倾向在很大程度上是由遗传因素决定的，独立于与主要精神障碍相关的那些因素。这项研究将在迄今为止为自杀行为研究收集的最大样本集合中筛选基因组，以确定责任基因。

DESCRIPTION (provided by applicant): This collaborative R01 involves three sites: New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., in New York City, USA (Mann), McGill University in Montreal, Canada (Turecki) and University of Munich, Germany (Rujescu) to examine the complex genetic basis of suicidal behavior. We have contributed to the original observations showing that suicide and nonfatal suicide attempts have biologic changes that are distinct from those of major psychiatric disorders that underlie suicide such as major depressive disorder or bipolar disorder. We have reported candidate gene associations that are independently associated with mood disorders or with suicide attempts. We believe the field is ready for a major effort to survey the genome to seek genes associated with suicidal behavior that are independent of the major psychiatric illnesses. We have developed and tested a potential predictive stress-diathesis model of suicidal behavior derived from a comprehensive assessment of risk factors. Depressed individuals with prominent (1) pessimism and (2) severity of life-time aggression/impulsivity are at greater risk for suicidal behavior and the effects are additive. These clinical phenotypic components can be measured in the field in patients and suicides. We now propose to use genome-wide screens to identify candidate genes and conserved haplotype blocks within those genes 4000 cases that span the higher severity range of suicidal behavior, namely completed suicide and attempted suicide compared to both psychiatrically matched controls and to healthy volunteers. We have data on Axis I and Axis II diagnoses and data on lifetime aggression scores and current severity of depression to permit assessment of these potential etiological factors and potential behavioral endophenotypes. We have data on childhood reported histories of physical or sexual abuse which will be a focus for an exploratory gene-early environment interaction analysis. Causal SNPs will be further identified by sequencing the most promising gene segments. PUBLIC HEALTH RELEVANCE: The predisposition to suicidal behavior is substantially determined by genetic factors independent of those associated with major psychiatric disorders. This study will screen the genome in the largest collection of samples ever assembled for such a study of suicidal behavior in order to identify the responsible genes.