Bühler Kora-Mareen, Giné Elena, Echeverry-Alzate Victor, Calleja-Conde Javier, de Fonseca Fernando Rodriguez, López-Moreno Jose Antonio
Department of Psychobiology, School of Psychology, Complutense University of Madrid, Málaga, Spain.
Department of Cellular Biology, School of Medicine, Complutense University of Madrid, Málaga, Spain.
Addict Biol. 2015 Sep;20(5):845-71. doi: 10.1111/adb.12204. Epub 2015 Jan 21.
Drug-related phenotypes are common complex and highly heritable traits. In the last few years, candidate gene (CGAS) and genome-wide association studies (GWAS) have identified a huge number of single nucleotide polymorphisms (SNPs) associated with drug use, abuse or dependence, mainly related to alcohol or nicotine. Nevertheless, few of these associations have been replicated in independent studies. The aim of this study was to provide a review of the SNPs that have been most significantly associated with alcohol-, nicotine-, cannabis- and cocaine-related phenotypes in humans between the years of 2000 and 2012. To this end, we selected CGAS, GWAS, family-based association and case-only studies published in peer-reviewed international scientific journals (using the PubMed/MEDLINE and Addiction GWAS Resource databases) in which a significant association was reported. A total of 371 studies fit the search criteria. We then filtered SNPs with at least one replication study and performed meta-analysis of the significance of the associations. SNPs in the alcohol metabolizing genes, in the cholinergic gene cluster CHRNA5-CHRNA3-CHRNB4, and in the DRD2 and ANNK1 genes, are, to date, the most replicated and significant gene variants associated with alcohol- and nicotine-related phenotypes. In the case of cannabis and cocaine, a far fewer number of studies and replications have been reported, indicating either a need for further investigation or that the genetics of cannabis/cocaine addiction are more elusive. This review brings a global state-of-the-art vision of the behavioral genetics of addiction and collaborates on formulation of new hypothesis to guide future work.
与药物相关的表型是常见的复杂且高度可遗传的性状。在过去几年中，候选基因研究（CGAS）和全基因组关联研究（GWAS）已鉴定出大量与药物使用、滥用或依赖相关的单核苷酸多态性（SNP），主要与酒精或尼古丁有关。然而，这些关联中很少有在独立研究中得到重复验证。本研究的目的是对2000年至2012年间在人类中与酒精、尼古丁、大麻和可卡因相关表型最显著相关的SNP进行综述。为此，我们选择了在同行评审的国际科学期刊上发表的候选基因研究、全基因组关联研究、基于家系的关联研究和病例对照研究（使用PubMed/MEDLINE和成瘾GWAS资源数据库），其中报道了显著关联。共有371项研究符合搜索标准。然后，我们筛选出至少有一项重复研究的SNP，并对关联的显著性进行荟萃分析。迄今为止，酒精代谢基因、胆碱能基因簇CHRNA5-CHRNA3-CHRNB4以及DRD2和ANK1基因中的SNP是与酒精和尼古丁相关表型最常重复且最显著的基因变异。在大麻和可卡因方面，报道的研究和重复验证的数量要少得多，这表明要么需要进一步研究，要么大麻/可卡因成瘾的遗传学更难以捉摸。本综述提供了成瘾行为遗传学的全球最新情况，并有助于提出新的假设以指导未来的工作。
