Genetic analysis of high-risk Utah suicide pedigrees

描述（由申请人提供）：自杀是一个重大的健康问题。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），约占全世界死亡人数的2%（世界卫生组织，2000年）。多个大型研究的汇总数据得出了完成自杀的遗传率估计为45%。落基山脉各州的年龄调整自杀率要高得多，犹他州一直排在前十。在犹他州，自杀是15至54岁男性死亡的主要原因。我们的项目将使用通过与集中的犹他州法医办公室（OME）的长期合作从死者身上收集的大量DNA资源。拥有DNA的2000名死者的记录与犹他州人口数据库（UPDB）相关联，UPDB是一个计算机化的家谱数据库，其中包括650多万人的医疗数据、人口统计信息和家谱数据。使用UPDB，我们确定了27个高风险家庭，其中包含约150名带有DNA的自杀死者。作为一种罕见的情况（每年1-2/10,000），高危谱系中自杀完成的汇总为研究危险因素提供了独特的资源。我们将使用UPDB中的家谱、人口统计和医学数据来识别和关注这些高风险自杀谱系中最引人注目的；与非家族性自杀相比，那些既包含大量自杀完成，又表现出最具歧视性的特征的人。通过使用这些表型比较来选择最独特的高风险谱系，我们将增加同质性并加强我们分离与自杀风险相关的遗传变异的能力。这些鉴别表型也将确定与高家族风险相关的非遗传因素

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.