Identifying Amphetamine Addiction Risk Variants by Whole Genome Sequencing

描述（申请人提供）：药物滥用和成瘾是社会的主要负担；据估计，美国每年仅经济成本就超过5000亿美元，其中包括健康、与犯罪有关的成本和生产力损失。全基因组关联（GWA）研究已经确定了大量常见的单核苷酸多态性（SNP）易感等位基因，可用于多种常见疾病。其中有几项是针对成瘾表型进行的，即吸烟和尼古丁依赖、酒精依赖、多种物质依赖和甲基苯丙胺依赖/滥用。已发现的最可靠的关联是CHRNA5/CHRNA3/CHRNB4、CHRNB3/CHRNA6和CYP2A6/CYP2B6区域与吸烟行为、尼古丁依赖和吸烟相关疾病之间的关联。虽然最近的GWA研究取得了令人印象深刻的成功，但这一图景显然是不完整的，而且遗传性的很大一部分仍未得到解释。在此，我们建议利用deCODE Genetics收集和开发的独特遗传资源，引领基于全基因组序列的人类成瘾遗传学，以发现影响成瘾风险的中等至罕见频率的遗传高风险变异。为此目的，我们的重点是在冰岛接受成瘾治疗的15 000多名特征明显的人口。使用新的大规模并行技术的全基因组测序现在是可行的。尽管成本正在迅速下降，但要对数千个个体的基因组进行完整测序仍然非常昂贵，而这是下一代强有力的疾病关联研究所必需的。利用Illumina SNP芯片的大量个体基因分型，广泛的冰岛家谱，以及最近的方法进步，我们已经能够系统可靠地对所有芯片分型个体的SNP基因分型进行全基因组分型。利用这些结果，并通过对来自安非他明高度依赖家庭的150名个体的全基因组测序，我们计划使用大有效样本量进行成瘾的全基因组关联研究，否则这些研究将会非常昂贵。我们将测序数据与冰岛家谱相结合的能力也允许检测具有亲代起源效应的成瘾变异，否则在标准关联分析中可能会遗漏这些变异。我们期望找到许多新的联系，新的类型，这将增加我们对成瘾和药物滥用的遗传学的理解。原始数据将被广泛地提供给其他人，以供他们在此基础上进行构建，随着序列被传递给更多的人，资源的价值将会增加。

DESCRIPTION (provided by applicant): Drug abuse and addiction are major burdens to society; economic costs alone are estimated to exceed half a trillion dollars annually in the United States, including health, crime-related costs, and losses in productivity. Genome-wide association (GWA) studies have identified a high number of common single nucleotide polymorphism (SNP) susceptibility alleles for a wide variety of common diseases. Of those, several have been performed for addiction phenotypes, i.e. smoking and nicotine dependence, alcohol dependence, polysubstance dependence and methamphetamine dependence/abuse. The most solid associations that have been discovered are between the CHRNA5/CHRNA3/CHRNB4, CHRNB3/CHRNA6 and CYP2A6/CYP2B6 regions and smoking behavior, nicotine dependence, and smoking-related diseases. While the success of recent GWA studies is impressive, the picture is clearly incomplete, and a substantial part of the heritability remains unaccounted for. We propose here to take advantage of the unique genetic resources gathered and developed at deCODE Genetics to lead the way into whole genome sequence-based human addiction genetics to uncover genetic high risk variants of moderate to rare frequency that affect the risk of addiction. To this end we focus on a well characterized population of over 15,000 that have been treated for addiction in Iceland. Whole genome sequencing using new massively parallel technologies is now feasible. Although costs are dropping rapidly, it is still very expensive to fully sequence the genomes of the thousands of individuals that are required for the next generation of well-powered disease association studies. Taking advantages of the large number of individuals genotyped using an Illumina SNP-chip, the extensive Icelandic genealogy, and recent methodological advances we have been able to systematically and reliably genome-wide phase the SNP genotypes for all the chip-typed individuals. Utilizing these results, and by sequencing the whole- genomes of 150 individuals from families with a high prevalence of amphetamine dependence we plan to perform whole-genome association studies of addiction with large effective sample sizes, studies that would otherwise be prohibitively costly. Our ability to phase the sequencing data together with the Icelandic genealogy also allows for detection of addiction variants with parental origin effect that are can otherwise be missed in standard association analysis. We expect to find many new associations, of novel types, that will increase our understanding of the genetics of addiction and drug abuse. The primary data will be made widely available for others to build on, and the resource will grow in value as the sequence is imputed into more people.