Genetic Dissection in Pedigrees of Substance Use and Mood Disorders Comorbidity

药物使用和情绪障碍合并症谱系的基因剖析

• 批准号: 9062049
• 负责人: NELSON B. FREIMER
• 金额: $ 10.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062049
• 关键词: Affect; Alcohol or Other Drugs use; Behavior Disorders; Bipolar Disorder; Brain Diseases; Chromosome Mapping; Clinical; Collection; Colombia; Comorbidity; Costa Rica; Data; Diagnosis; Diagnostic; Disease; Dissection; Etiology; Evaluation; Family; First Degree Relative; Fright; Future; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Grant; Health; Heritability; Individual; Investigation; Joints; Major Depressive Disorder; Maps; Measures; Modeling; Mood Disorders; NIH Program Announcements; National Institute of Drug Abuse; Outcome; Persons; Phenotype; Population; Psychiatric Diagnosis; Public Health; Recording of previous events; Recruitment Activity; Relative (related person); Research Infrastructure; Resolution; Risk; SNP genotyping; Sample Size; Sampling; Sampling Studies; Sequence Analysis; Societies; Staging; Substance Addiction; Substance Use Disorder; Substance abuse problem; Time; Variant; base; burden of illness; endophenotype; follow-up; genetic analysis; genetic pedigree; genetic variant; genome sequencing; genome-wide; member; prevent; trait

 DESCRIPTION (provided by applicant): This project aims to identify genetic variants that contribute to the comorbidity of substance use disorders (SUD) and mood disorders (MD). Each of these disorders represents among the greatest disease burdens worldwide. Yet their frequent co-morbidity is itself a major public health problem: individuals in whom SUD and MD co-occur have clinical outcomes that are dramatically worse than those of individuals who suffer from only one of these conditions. Our limited understanding of the factors that generate SUD/MD co-morbidity hinders our ability to prevent it or to successfully treat affected individuals. In particular, although both types of disorder are highly heritable, it remains unclear whether the set of genetic variants influencing risk for SUD overlaps with the genetic variants contributing to risk for MD, or even whether there are variants that specifically predispose to SUD/MD co-morbidity. To elucidate the genetic basis of SUD/MD comorbidity this project will analyze comprehensive genetic variation data obtained through whole genome sequencing (WGS) of members of 26 pedigrees from the genetically related population isolates of Antioquia, Colombia (CO) and the Central Valley of Costa Rica (CR). The project will leverage the infrastructure and data (extensive phenotypes, high-resolution genome-wide genotypes, and deep WGS) from an existing study of 800 individuals in these pedigrees that has focused on identifying genetic variants contributing to severe bipolar disorder (BP-I) and has already genetically mapped loci for both BP-I and for BP-I endophenotypes. The majority of BP-I individuals worldwide demonstrate comorbidity with one or more SUD, and preliminary data indicate that these pedigrees include a substantial number of members comorbid for SUD with either BP-I or another form of MD. To conduct genetic investigations of SUD/MD comorbidity this project will: 1) Recruit 300 additional 1st degree relatives of existing subjects, targeting individuals affected with SUD and a broad spectrum of MD, achieving a total sample of 1100 individuals; 2) Conduct phenotypic assessments in the 1100-person sample to quantify substance use, diagnose SUD, and identify heritable endophenotypes for SUD and SUD/MD comorbidity; 3) Perform additional genotyping and WGS to achieve comprehensive genetic variation data for the entire 1100-person sample; 4) Carry out genetic mapping studies to identify variants contributing to SUD, SUD/MD comorbidity, and to SUD-related endophenotypes. Future studies will follow-up our results in a variety of independent study samples from CO, CR and the U.S.

 描述(由申请人提供)：该项目旨在确定导致物质使用障碍(SUD)和情绪障碍(MD)共病的基因变异。这些疾病中的每一种都是世界上最大的疾病负担之一。然而，他们频繁的共同发病本身就是一个重大的公共卫生问题：同时发生SUD和MD的人的临床结果比只患有其中一种情况的人严重得多。我们对导致SUD/MD共病的因素的有限理解阻碍了我们预防或成功治疗受影响的个体的能力。特别是，虽然这两种类型的疾病都具有很高的遗传性，但目前尚不清楚影响sud风险的一组遗传变异是否与导致 MD的风险，甚至是否存在特别容易导致SUD/MD共病的变异。为了阐明SUD/MD共病的遗传基础，本项目将分析来自哥伦比亚安蒂奥基亚(CO)和哥斯达黎加中央山谷(CR)遗传相关群体分离株的26个家系成员通过全基因组测序获得的全面遗传变异数据。该项目将利用现有研究中的基础设施和数据(广泛的表型、高分辨率的全基因组基因类型和深层WGS)，该研究对这些家系中的800个个体进行了研究，重点是识别导致严重双相情感障碍(BP-I)的遗传变异，并已经绘制了BP-I和BP-I内表型的遗传图谱。全世界大多数BP-I患者表现出与一个或多个SUD的共病，初步数据表明，这些家系包括相当数量的成员患有SUD和BP-I或其他形式的MD。为了进行SUD/MD共病的遗传学调查，该项目将：1)招募300名现有受试者的一级亲属，目标是受影响的个人 对所有1100人样本进行表型评估，以量化物质使用情况，诊断SUD和SUD/MD共病的可遗传的内表型；3)进行额外的基因分型和WGS，以获得整个1100人样本的全面遗传变异数据；4)进行基因图谱研究，以确定导致SUD、SUD/MD共病的变种，以及与SUD相关的内表型。未来的研究将在来自CO、CR和美国的各种独立研究样本中跟进我们的结果。