Suicidal Behavior in Mood Disorders: Genes and Intermediate Phenotypes

描述（由申请人提供）：该合作R 01涉及三个地点：纽约州精神病研究所/精神卫生研究基金会，Inc.，在美国纽约市（Mann）、加拿大蒙特利尔麦吉尔大学（Turecki）和德国慕尼黑大学（Rujescu）进行的一项研究，以研究自杀行为的复杂遗传基础。我们对最初的观察结果做出了贡献，这些观察结果表明，自杀和非致命性自杀企图的生物学变化与导致自杀的主要精神疾病（如重度抑郁症或双相情感障碍）的生物学变化不同。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努力，调查基因组，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。我们已经开发并测试了一个潜在的预测压力素质模型的自杀行为来自一个全面的评估风险因素。抑郁的个体具有突出的（1）悲观主义和（2）严重的终身攻击/冲动性，自杀行为的风险更大，并且影响是累加的。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，以确定候选基因和保守的单倍型块在这些基因4000例，跨越更高的严重程度范围的自杀行为，即完成自杀和自杀未遂相比，精神病学匹配的控制和健康志愿者。我们有关于轴I和轴II诊断的数据，以及关于终生攻击评分和抑郁症当前严重程度的数据，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，将进一步确定因果SNP。公共卫生相关性：自杀行为的倾向性基本上是由遗传因素决定的，与主要精神疾病无关。这项研究将在有史以来为自杀行为研究收集的最大样本中筛选基因组，以确定负责的基因。

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.