Genetics of Opioid Dependence

阿片类药物依赖的遗传学

• 批准号: 9301731
• 负责人: JOEL GELERNTER
• 金额: $ 6.28万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-05 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301731
• 关键词: Accounting; Address; Affect; African; African American; Alcohols; Behavior; Binding; Biological; Biological Assay; Biology; Candidate Disease Gene; Cannabis; Chromosome Mapping; Clinical; Cocaine; Code; Collaborations; Collection; Complex; Copy Number Polymorphism; DISC1 gene; Data; Detection; Electrophoretic Mobility Shift Assay; European; Exons; Genes; Genetic; Genetic Risk; Genome; Genomic Segment; Genomics; Genotype; Health; Heritability; In Vitro; Individual; Investigation; Mental disorders; Methods; Nicotine; Opiate Addiction; Opioid; Phenotype; Procedures; Public Health; Refractory; Regulatory Element; Research; Research Personnel; Risk; Risk Factors; SNP genotyping; Sampling; Siblings; Societies; Substance Addiction; Techniques; Testing; Variant; Work; base; case control; cost; cost effective; deep sequencing; disorder risk; exome; exome sequencing; experience; follow-up; genetic linkage analysis; genome analysis; genome wide association study; genome-wide; improved; next generation sequencing; opioid use; programs; promoter; rare variant; risk variant; targeted sequencing; trait

DESCRIPTION (provided by applicant): Opioid dependence (OD) is prevalent in the US and worldwide, and is highly destructive and costly to individuals and to society. It is also moderatel heritable. In prior iterations of this research program, we: 1) collected a sample of affected sibling pairs and carried out linkage analysis of OD and related traits and 2) collected a case-control sample and carried out numerous candidate gene investigations and a genomewide association study. Although we have identified chromosomal regions and specific risk alleles related to OD (both common and rare variants), our findings (and those of other investigators using similar approaches) have accounted for only a small part of OD heritability. Understanding the genetic risk of OD, like that of most complex traits, has proven refractory to the application of linkage and association techniques only. In this proposal, we describe a plan to identify additional OD risk factors. The clinical samples we have ascertained previously are distinguished by deep phenotypic characterization and high representation of African-Americans (AAs), who are underrepresented in GWAS, including substance dependence (SD) GWAS. We propose to identify rare (and possibly common) variants and structural (including copy number) variants by means of next generation sequencing of a set of these subjects: 3000 full exomes (2000 cases and 1000 controls, 1/3 of whom will be AA). Identified putative risk variants will be genotyped in our larger sample of >9500 subjects and evaluated for association to OD and other SD traits. We will follow up both our recent genomewide-significant GWAS results, and results identified by exome sequencing, with deep sequencing in the entire sample. Finally, all sequence data will be made publicly available. This project has the potential to identify the next significant pool of OD genetic risk variants, thus advancing the field, with resulting improved understanding of biology, and consequent applications to public health.

描述（由申请人提供）：阿片类药物依赖 (OD) 在美国和世界范围内普遍存在，对个人和社会具有高度破坏性和高昂代价。它也是中等遗传的。在该研究计划的先前迭代中，我们：1) 收集了受影响兄弟姐妹对的样本，并对 OD 和相关性状进行了连锁分析，2) 收集了病例对照样本，并进行了大量候选基因调查和全基因组关联研究。尽管我们已经确定了与 OD 相关的染色体区域和特定风险等位基因（常见和罕见变异），但我们的研究结果（以及使用类似方法的其他研究人员的研究结果）仅占 OD 遗传力的一小部分。与大多数复杂性状一样，了解 OD 的遗传风险已被证明仅应用连锁和关联技术是难以实现的。在本提案中，我们描述了一项识别其他 OD 风险因素的计划。我们之前确定的临床样本具有深层表型特征和非裔美国人 (AA) 的高代表性，这些人在 GWAS 中代表性不足，包括物质依赖 (SD) GWAS。我们建议通过对一组受试者进行下一代测序来识别罕见（也可能是常见）变异和结构（包括拷贝数）变异：3000 个完整外显子组（2000 个病例和 1000 个对照，其中 1/3 将是 AA） ）。确定的假定风险变异将在超过 9500 名受试者的更大样本中进行基因分型，并评估其与 OD 和其他 SD 性状的关联。我们将跟进最近的全基因组显着 GWAS 结果以及外显子组测序鉴定的结果，并对整个样本进行深度测序。最后，所有序列数据将公开。该项目有可能确定下一个重要的 OD 遗传风险变异库，从而推进该领域的发展，从而提高对生物学的理解，并随后在公共卫生中应用。