Abstract

Genome-wide studies provide increasing evidence of association of genetic variants with different behaviors. However, there is a growing need for replication and subsequent characterization of specific findings. In this sense, the CHRNA5 gene has been associated with nicotine (with genome-wide significance), alcohol and cocaine addictions. So far, this gene has not been evaluated in smoked (crack) cocaine. We aimed to analyze the influence of CHRNA5 variants in crack addiction susceptibility and severity. The sample includes 300 crack-addicted patients and 769 non-addicted individuals. The CHRNA5 SNPs evaluated were rs588765, rs16969968, and rs514743. Homozygosity for rs16969968 and rs588765 major alleles was nominally associated with a risk to crack addiction (GG, P = 0.032; CC, P = 0.036, respectively). Haplotype analyses reveal significant associations (rs588765|rs16969968|rs514743 p_{global-corrected} = 7.66 × 10^–5) and suggest a substantial role for rs16969968. These findings corroborate previous reports in cocaine addiction—in line with the expected effects of cocaine in the cholinergic system—and in the opposite direction of significant GWAS findings for nicotine addiction susceptibility. These results are strengthened by the first report of an association of rs588765 with crack addiction and by the haplotype findings. In summary, our study highlights the relevance of the α5 subunit on crack cocaine addiction, replicating previous results relating CHRNA5 with the genetics and pathophysiology of addiction of different drugs.

中文翻译：

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CHRNA5 基因变体与可卡因成瘾的关联。

摘要

全基因组研究提供了越来越多的证据表明遗传变异与不同行为之间存在关联。然而，对特定发现的复制和后续表征的需求日益增长。从这个意义上说，CHRNA5基因与尼古丁（具有全基因组意义）、酒精和可卡因成瘾有关。到目前为止，尚未在吸食（快克）可卡因中评估该基因。我们旨在分析CHRNA5变体对破解成瘾易感性和严重性的影响。样本包括 300 名瘾君子和 769 名非瘾君子。该CHRNA5评估的 SNP 为 rs588765、rs16969968 和 rs514743。rs16969968 和 rs588765 主要等位基因的纯合性名义上与成瘾风险相关（GG，P  = 0.032；CC，P  = 0.036，分别）。单倍型分析揭示了显着的关联 (rs588765|rs16969968|rs514743 p _{global-corrected}  = 7.66 × 10 ^–5) 并建议 rs16969968 发挥重要作用。这些发现证实了先前关于可卡因成瘾的报告——与可卡因在胆碱能系统中的预期作用一致——并且与 GWAS 对尼古丁成瘾易感性的重要发现相反。rs588765 与裂纹成瘾的关联的第一份报告和单倍型发现加强了这些结果。总之，我们的研究强调了 α5 亚基与可卡因成瘾的相关性，复制了先前将CHRNA5与不同药物成瘾的遗传学和病理生理学相关的结果。