Genetic analysis of high-risk Utah suicide pedigrees

描述(申请人提供)：自杀是一个重要的健康问题。美国每年有超过33,000人自杀死亡，占所有死亡人数的1.3%(WISQARS，2005年)，约占全球死亡人数的2%(世界卫生组织，2000年)。综合多项大型研究的数据，完全自杀的遗传率估计为45%。落基山脉各州经年龄调整后的自杀率要高得多，犹他州一直位居前十。在犹他州，自杀是15岁至54岁男性的主要死因。我们的项目将使用已经通过与犹他州中央法医办公室(OME)的长期合作从死者身上收集的大量DNA资源。2,000名携带DNA的死者的记录被链接到犹他州人口数据库(UPDB)，这是一个计算机化的家谱数据库，包括超过650万人的医疗数据、人口信息和家谱数据。使用UPDB，我们确定了27个高危家庭，其中包含约150名携带DNA的自杀死者。作为一种罕见的情况(每年1-2/10,000)，高危家系中自杀完成率的聚集是研究危险因素的独特资源。我们将使用UPDB中的系谱、人口统计学和医学数据来识别和关注这些高危自杀家系中最引人注目的；这些家系既包含显著的过度自杀完成，又表现出与非家族性自杀相比最具区别性的特征。通过使用这些表型比较来选择最独特的高危家系，我们将增加同质性，并加强我们分离与自杀风险相关的基因变异的能力。这些区分表型还将确定与高家族风险相关的非遗传因素。 这可以促进其他流行病学研究，并有助于未来的基因x环境分析。我们目前手头有来自犹他州另外2500名自杀死者的大量DNA和表型信息。到研究结束时，这个样本将增长到4000多个DNA，这是有史以来收集到的最大的基于人群的自杀死者DNA样本。我们建议将重点放在具有更多穿透性罕见基因变异可能性增加的不寻常的高风险自杀家系上，然后对犹他州的大量死者和公开可用的精神病学数据集进行确认和后续分析。检测与自杀相关的基因变异可以揭示导致人群自杀风险的生物路径，或与特定疾病相关的生物路径。我们选择了最先进的分析方法，并组建了一个专家团队(分析、表型和分子)来探索这些独特的数据资源，以确定自杀的遗传危险因素。这个 检测与自杀相关的罕见变异可以揭示导致人群自杀风险的生物学途径，或与特定疾病有关的生物途径。

DESCRIPTION (provided by applicant): Suicide is a significant health concern. There are over 33,000 suicide deaths per year in the United States, accounting for 1.3% of all fatalities (WISQARS, 2005), and about 2% of deaths worldwide (World Health Organization, 2000). Aggregated data across multiple large studies has produced heritability estimates of completed suicide of 45%. The Rocky Mountain States have much higher age-adjusted suicide rates, and Utah is consistently in the top ten. In Utah, suicide is the leading cause of death for males between the ages of 15 and 54. Our project will use a large DNA resource already collected from decedents through a long-term collaboration with the centralized Utah State Office of the Medical Examiner (OME). Records of >2,000 decedents with DNA were linked to the Utah Population DataBase (UPDB), a computerized genealogy database that includes medical data, demographic information, and genealogical data for over 6.5 million individuals. Using the UPDB, we identified 27 high risk families containing ~150 suicide decedents with DNA. As a rare condition (1-2/10,000 per year), aggregation of suicide completion in high-risk pedigrees represents a unique resource to study risk factors. We will use the genealogical, demographic, and medical data in the UPDB to identify and focus on the most compelling of these high-risk suicide pedigrees; those that contain both a significant excess of suicide completion and that exhibit the most discriminating characteristics compared to non-familial suicide. By using these phenotypic comparisons to choose the most unique high-risk pedigrees, we will increase homogeneity and strengthen our ability to isolate genetic variants related to suicide risk. These discriminating phenotypes will also identify non-genetic factors associated with high familial risk that can foster other epidemiological studies, and can facilitate future gene x environment analyses. We currently have in hand a large resource of DNA and phenotype information from ~2500 additional Utah suicide decedents. This sample will grow to over 4000 DNAs by the end of the study, the largest population-based sample of DNA from suicide decedents ever collected. We propose to focus on unusual high-risk suicide pedigrees with increased likelihood for more penetrant rare genetic variation, followed by confirmation and follow-up analyses in large cohorts of Utah decedents and publicly-available psychiatric data sets. The detection of genetic variants associated with suicide could shed light on biological pathways leading to suicide risk in the population, or in association with specific disorders. We have chosen state-of-the-art analytical methods, and have assembled a team of experts (analytic, phenotypic, and molecular) to explore these unique data resources to identify genetic risk factors for suicide. The detection of rare variants associated with suicide could shed light on biological pathways leading to suicide risk in the population, or in association with specific disorders.