Genomewide Association Study of Cocaine Dependence in two Populations

描述(申请人提供)：两个人群中可卡因依赖的全基因组关联研究摘要：可卡因依赖(CD)对社会造成极高的代价；遗传流行病学研究支持这一特征的适度遗传性。我们已经完成了这一性状的全基因组连锁研究，并提出了几个候选基因关联。Cd影响了整个社会；然而，少数群体，特别是非洲裔美国人，尽管受到Cd的影响很高，但特别是研究不足。我们已经非常成功地收集了物质依赖(SD)EA和AA无关的对象和家族，并在此基础上提出了AA和EA样本中CD的全基因组关联研究(GWAS)。使用严格可靠的SSADDA量表对受试者进行评估。由于尼古丁依赖(ND)与CD存在实质性的共病(这也是适度可遗传的)，我们建议将ND的全基因组关联分析作为次要目标(正如我们在先前的连锁研究中类似并成功地完成的)。我们最初的样本规模为3500名CD患者(2000名AA和1500名EA)和3075名ND患者(1575名AA和1500名EA)(许多人同时患有这两种特征)，与由我们招募的受试者和我们的合作者Li组成的对照样本相比，将提供足够的能力来检测这两个特征的新风险基因座，其中AA对照样本增加了已在公共领域(PD)中的基因。我们已经组装了1400个AA对照和1600个EA对照(作为公开数据的项目成果的一部分，已经在Affymetrix 6.0阵列上对979个AA受试者进行了基因分型)；和&gt；1600个EA对照。我们建议在Affymetrix 6.0阵列上对AA受试者进行分型，在Illumina 1M阵列上对EA受试者进行分型。这将在每个人口中提供最好的可用覆盖率，同时允许与现有的PD样本进行最好的可比性。对于复制，我们已经收集了额外的&gt；2350个CD受试者(包括1100个SSADDA评估的受试者，这不是初始GWAS所需的)和&gt；1400个对照的集合，将用定制的1536-SNP阵列进行研究。此外，李博士还同意对自己样本中的任何ND发现进行独立评估。最后，我们将使用NimbleGen HD2高密度寡核苷酸微阵列对500例患者和500名对照进行高分辨率CNV全基因组评估。这将使我们能够考虑额外的多态变异来源，分辨率要高得多，整个基因组的一致性也更高，甚至比现代高密度基因分型阵列也能获得。这将是一次开创性的CD GWAS，尤其值得注意的是它侧重于少数群体中的两个主要物质依赖特征。因此，我们希望在美国主要人口中获得关于CD的宝贵新见解。后续计划包括在独立样本中复制和对相关基因组区域进行高通量测序(后者与本提案分开)。 公共卫生相关性：叙述该项目的主要目标是利用全基因组关联研究技术，确定与可卡因依赖相关的风险基因和变异。第二个目标是确定尼古丁依赖的风险基因和变种。发现这些风险基因将有助于了解、预防并最终治疗这些疾病。

DESCRIPTION (provided by applicant): Genomewide association study of cocaine dependence in two populations Abstract: Cocaine dependence (CD) is highly costly to society; genetic epidemiologic studies support moderate heritability for this trait. We have completed a genomewide linkage study for this trait, and several candidate gene associations have been proposed. CD cuts across society; however, minority populations, and specifically African-Americans (AAs), though affected by CD at high rates, are particularly understudied. We have been very successful at collecting substance-dependent (SD) EA and AA unrelated subjects and families, and based on that sample, we propose a genomewide association study (GWAS) of CD in both AA and EA samples. Affected subjects were assessed with the rigorous and reliable SSADDA instrument. Because there is substantial comorbidity of nicotine dependence (ND) (which is also moderately heritable) with CD, we propose genomewide association analysis of ND as a secondary aim (as we have similarly, and successfully, done in prior linkage studies). Our initial sample size of a total of 3500 subjects with CD (2000 AA and 1500 EA), and 3075 subjects with ND (1575 AA and 1500 EA) (with many individuals comorbid for the two traits), will provide adequate power to detect novel risk loci for both traits, when compared to control samples composed of subjects recruited by ourselves, and our collaborator Ming D. Li, with the AA control sample augmented with genotypes already in the public domain (PD). We have assembled >1400 AA controls to genotype (979 AA subjects already been genotyped on the Affymetrix 6.0 array as part of project GAIN with data publicly available); and >1600 EA controls. We propose to genotype AA subjects on the Affymetrix 6.0 array, and EA subjects on the Illumina 1M array. This will provide best available coverage in each population, and at the same time allow best possible comparability with existing PD samples. For replication, we have assembled a collection of an additional >2350 CD subjects (including 1100 SSADDA-assessed subjects not required for the initial GWAS) and >1400 controls, to be studied with a custom 1536-SNP array. Additionally, Dr. Li has agreed to evaluate independently any ND findings in his own sample. Finally, we will conduct a high-resolution CNV genomewide assessment using NimbleGen HD2 high- density oligonucleotide microarrays on a subset of 500 cases and 500 controls. This will allow us to consider an additional source of polymorphic variation at much higher resolution, and with greater uniformity across the genome, than can be obtained even with modern high-density genotyping arrays. This will be a pioneering CD GWAS, and is particularly noteworthy for its focus on two major substance dependence traits in a minority population. We therefore expect to obtain invaluable new insights into CD in the major US populations. Follow-up plans include replication in an independent sample and high-throughput sequencing of implicated genomic regions (the latter separate from the present proposal). PUBLIC HEALTH RELEVANCE: Narrative The major goal of this project is to identify risk genes and variants associated with cocaine dependence, using the genomewide association study technique. A secondary goal is to identify risk genes and variants for nicotine dependence. Finding these risk genes will aid in understanding, prevention, and eventually, treatment, of these disorders.