Deep sequencing studies for cannabis and stimulant dependence

大麻和兴奋剂依赖的深度测序研究

• 批准号: 8268314
• 负责人: CINDY L EHLERS
• 金额: $ 338.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268314
• 关键词: Affect; African American; Alcohols; American; Blood specimen; Cannabis; Cell Line; Clinical; Cocaine; Cocaine Dependence; Cohort Studies; Comorbidity; Connecticut; DNA; DNA Sequence Analysis; Data; Data Set; Dependence; Development; Diagnosis; Diagnostic and Statistical Manual; Drug Addiction; Economics; European; Event; Exhibits; Family; Family Study; Functional disorder; Gene Amplification; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Genotype; Goals; Haplotypes; Heritability; Illicit Drugs; Individual; Informatics; Institution; Marijuana Dependence; Methamphetamine; Methodology; Methods; Minor; Mission; Missouri; National Institute of Drug Abuse; Native Americans; Nicotine; Opiate Addiction; Opioid; Other Genetics; Phase; Phenotype; Population; Population Characteristics; Population Study; Predisposition; Prevention strategy; Procedures; Psychostimulant dependence; Public Health; Qualifying; Research; Research Infrastructure; Research Institute; Research Proposals; Rest; Sampling; Sampling Studies; San Francisco; Secure; Sequence Analysis; Site; Source; Structure; Substance of Abuse; Symptoms; Technology; Testing; Universities; Variant; addiction; base; case control; cohort; computer infrastructure; cost; data reduction; data sharing; genetic linkage analysis; genetic risk factor; genome sequencing; genome wide association study; genome-wide; insight; interest; methamphetamine abuse; microdeletion; next generation; public health relevance; response; simulation; theories; trait; treatment strategy

DESCRIPTION (provided by applicant): The goal of this proposal is to identify genes that affect susceptibility to stimulant and cannabis dependence using whole genome sequencing with genotype imputation. The advent of increasingly economical whole genome sequencing provides new opportunities to identify trait-associated sequence variations not detected by linkage or association methods. It is not certain, however, what the most effective analytic method for identifying trait-related loci will be. Thus, we propose to study four distinct analytic approaches to identify sequence variants that affect stimulant and cannabis dependence in three cohorts using a state-of-the-art informatics infrastructure. The three study cohorts were ascertained as part of the Mission Indian Study (PI Cindy Ehlers), the combined Yale-University of Connecticut Addiction Study samples (PI Joel Gelernter) and the San Francisco Family Study (PI Kirk Wilhelmsen). Because we are studying populations with three different continental origins, we will ascertain whether the major genetic risk factors for the traits of interest are shared or population-specific. Two of the three populations that make up our sample (i.e., Native Americans and African Americans) are understudied. Inclusion of these cohorts will allow for analyses within and across populations that differ in ascertainment strategies and ethnic composition, permitting strong tests of replication across populations and enabling direct comparisons of ascertainment and analytic approaches as they apply to genetic studies of addiction. We expect that the approach used for this study will evolve. Currently we plan to use four complementary analytic strategies: 1) a conventional SNP analysis of genotypes detected using >5X sequence coverage for polymorphisms with minor allele frequency (MAF) greater than 0.1%; 2) a gene-based approach to determine whether more cases than controls have rare sequence variants (MAF<1%) likely to affect the function of a given gene; 3) use of a simplified form of affected-only linkage analysis of known and distantly related individuals to identify long chromosomal segments that are likely to be shared identical by descent; and 4) extended analysis of higher-level structural variation. The technology and economics of DNA sequence analysis is rapidly evolving. Based on current costs we plan to complete >5X whole genome sequencing of at least 3000 subjects. Critical to our decision to pursue low-pass genomic sequencing was the development of multipoint imputation methods. Simulation analysis indicates that for the same cost more subjects can undergo >5X whole genome sequencing with imputation than exomic sequencing, thus providing more exomic data as well as rich data for the rest of the genome. The findings from this study may provide insight into the genetics of other substances of abuse which can be confirmed by data sharing with other projects responding to this RFA and to other projects in the NIDA Genetics Consortium. PUBLIC HEALTH RELEVANCE: Cannabis and stimulants (methamphetamine and cocaine) are the most commonly used illicit drugs worldwide, and thus pose significant public health issues. Because cannabis and stimulant dependence have a substantial shared genetic etiology and exhibit significant genetic correlations with other drug dependencies, identifying sequence variants that affect cannabis and stimulant dependence should provide insights into the pathophysiology of dependence and inform prevention and treatment strategies.

描述（由申请人提供）：该提案的目的是鉴定使用与基因型插补的整个基因组测序有关刺激性和大麻依赖性敏感性的基因。越来越经济的整个基因组测序的出现提供了新的机会，可以识别未通过链接或关联方法检测到的与性状相关的序列变化。但是，不确定哪种最有效的分析方法是识别与性状相关的基因座的含义。因此，我们建议研究四种不同的分析方法，以鉴定使用最新信息基础设施在三个同类中影响刺激性和大麻依赖性的序列变体。确定了三项研究人群作为印度任务研究的一部分（PI Cindy Ehlers），康涅狄格州成瘾研究样本（PI Joel Gelernter）和旧金山家族研究（Pi Kirk Wilhelmen）的耶鲁大学合并。因为我们正在研究具有三种不同大陆源的人群，所以我们将确定感兴趣特征的主要遗传危险因素是共享的还是特定于人群的。构成我们样本的三个人群中的两个（即美洲原住民和非裔美国人）进行了研究。包含这些队列将允许在确定策略和种族组成不同的人群内部和跨种群中进行分析，从而允许对种群的重复进行强有力测试，并可以直接比较确定性和分析方法，因为它们适用于成瘾的遗传研究。我们希望该研究使用的方法将不断发展。目前，我们计划使用四种互补的分析策略：1）对使用> 5倍序列覆盖率检测到的基因型的常规SNP分析，用于次要等位基因频率（MAF）大于0.1％的多态性； 2）一种基于基因的方法来确定更多的病例比对照组是否具有罕见的序列变异（MAF <1％）可能影响给定基因的功能； 3）使用简化形式的仅受影响的已知和远距离相关个体的仅链接分析来识别可能通过下降共享相同的长染色体段； 4）更高级别结构变化的扩展分析。 DNA序列分析的技术和经济学正在迅速发展。根据当前的成本，我们计划完成至少3000名受试者的全基因组测序> 5倍。对于我们追求低通pass基因组测序的决定至关重要的是多点插补方法的发展。仿真分析表明，在相同的成本中，更多的受试者可以进行> 5倍的整个基因组测序，而不是外部测序，从而为其余基因组提供了更多的外部数据和丰富的数据。这项研究的发现可能会洞悉其他滥用物质的遗传学，这些物质可以通过与对该RFA的其他项目以及对NIDA遗传学财团中其他项目的数据共享证实。 公共卫生相关性：大麻和兴奋剂（甲基苯丙胺和可卡因）是全球最常用的非法药物，因此构成了重大的公共卫生问题。由于大麻和兴奋剂依赖性具有大量共同的遗传病因，并且与其他药物依赖性表现出显着的遗传相关性，因此鉴定影响大麻和兴奋剂依赖性的序列变异应提供对依赖性病理生理学的见解，并为预防和治疗策略提供了信息。