Suicidal Behavior in Mood Disorders: Genes and Intermediate Phenotypes

描述（由申请人提供）：该合作R01涉及三个地点：美国纽约市的纽约州精神病学研究所/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，这些观察表明，自杀和非致命性自杀企图具有不同于导致自杀的主要精神疾病（如重度抑郁症或双相情感障碍）的生物学变化。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，这个领域已经准备好进行一项重大努力，调查基因组，寻找与自杀行为相关的基因，这些基因与主要精神疾病无关。我们已经开发并测试了一种潜在的预测自杀行为的压力素质模型，该模型来源于对危险因素的综合评估。具有(1)悲观情绪和(2)终身攻击性/冲动性严重程度的抑郁个体有更高的自杀行为风险，且两者具有叠加效应。这些临床表型成分可以在患者和自杀者的现场测量。我们现在建议使用全基因组筛选来鉴定候选基因和这些基因中的保守单倍型块，这些病例跨越了自杀行为的较高严重程度范围，即完成自杀和企图自杀，与精神匹配的对照组和健康志愿者相比。我们有坐标轴I和坐标轴II的诊断数据，以及终生攻击得分和当前抑郁症严重程度的数据，以评估这些潜在的病因因素和潜在的行为内表型。我们有儿童报告的身体虐待或性虐待的历史数据，这将是探索性基因-早期环境相互作用分析的重点。通过对最有希望的基因片段进行测序，将进一步确定致病单核苷酸多态性。公共卫生相关性：自杀倾向基本上是由遗传因素决定的，与主要精神疾病无关。这项研究将筛选迄今为止为此类自杀行为研究收集的最大样本中的基因组，以确定负责任的基因。

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.