Identifying Amphetamine Addiction Risk Variants by Whole Genome Sequencing

描述(申请人提供)：吸毒和上瘾是社会的主要负担；在美国，仅经济成本估计就超过每年5000亿美元，包括健康、与犯罪相关的成本和生产力损失。全基因组关联(GWA)研究已经确定了多种常见疾病的大量常见单核苷酸多态(SNP)易感等位基因。其中，有几项是针对成瘾表型，即吸烟和尼古丁依赖、酒精依赖、多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系。虽然最近GWA研究的成功令人印象深刻，但这幅图景显然是不完整的，很大一部分遗传性仍未得到解释。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到罕见频率的遗传高危变异。为此，我们把重点放在冰岛接受过毒瘾治疗的15,000多人的特征良好的人群上。使用新的大规模并行技术进行全基因组测序现在是可行的。尽管成本正在迅速下降，但对下一代强大的疾病关联研究所需的数千个个体的基因组进行完整测序仍然非常昂贵。利用使用Illumina SNP芯片进行基因分型的大量个体，广泛的冰岛系谱和最近的方法学进步，我们已经能够系统和可靠地在全基因组范围内为所有芯片型个体进行SNP基因分型。利用这些结果，并通过对来自苯丙胺依赖高发家庭的150个人的全基因组测序，我们计划对大有效样本量的成瘾进行全基因组关联研究，否则研究费用将高得令人望而却步。我们将测序数据与冰岛家谱相结合的能力还允许检测具有父母起源影响的成瘾变异，否则在标准关联分析中可能会遗漏这些变异。我们希望找到许多新的关联，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。主要数据将被广泛提供给其他人进行建设，随着序列被赋予更多的人，资源的价值将会增长。

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.