Genomewide Association Study of Cocaine Dependence in two Populations

摘要：可卡因依赖（CD）是一种代价高昂的社会行为；遗传流行病学研究支持该性状的中度遗传性。我们已经完成了该性状的全基因组连锁研究，并提出了几个候选基因关联。CD影响整个社会；然而，少数民族人群，特别是非洲裔美国人（AAs），虽然受乳糜泻影响的比例很高，但研究尤其不足。我们已经非常成功地收集了物质依赖（SD） EA和AA无关的受试者和家族，并基于该样本，我们提出了AA和EA样本中CD的全基因组关联研究（GWAS）。采用严格可靠的SSADDA仪器对受影响的受试者进行评估。由于尼古丁依赖（ND）（也具有中度遗传性）与CD存在大量共病，因此我们建议将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那样）。我们的初始样本量为3500名CD患者（2000 AA和1500 EA）和3075名ND患者（1575 AA和1500 EA）（许多人同时患有这两种特征），与我们和我们的合作者Ming D. Li招募的受试者组成的对照样本（AA对照样本增加了已经在公共领域（PD）的基因型）相比，将提供足够的能力来检测这两种特征的新风险位点。我们收集了bb0 1400名AA对照进行基因分型（979名AA受试者已经在Affymetrix 6.0阵列上进行了基因分型，作为GAIN项目的一部分，数据已公开）；bbb1600ea控制。我们建议在Affymetrix 6.0芯片上对AA受试者进行基因分型，在Illumina 1M芯片上对EA受试者进行基因分型。这将在每个人群中提供最佳的可用覆盖率，同时允许与现有PD样本的最佳可比性。为了复制，我们收集了额外的>2350名CD受试者（包括1100名不需要初始GWAS的ssadda评估受试者）和>1400名对照，用定制的1536-SNP阵列进行研究。此外，李博士已同意独立评估他自己样本中的任何ND发现。最后，我们将使用NimbleGen HD2高密度寡核苷酸微阵列对500例病例和500例对照进行高分辨率CNV全基因组评估。这将使我们能够以更高的分辨率考虑多态性变异的额外来源，并且在整个基因组中具有更大的一致性，甚至可以用现代高密度基因分型阵列获得。这将是一个开创性的CD GWAS，特别值得注意的是，它关注的是少数群体的两个主要物质依赖特征。因此，我们期望对美国主要人群的乳糜泻获得宝贵的新见解。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（后者与本建议分开）。

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.