Data_Sheet_1_The Vulnerability to Methamphetamine Dependence and Genetics: A Case-Control Study Focusing on Genetic Polymorphisms at Chromosomal Region 5q31.3.docx

ObjectivesMethamphetamine (METH) is a central nervous psychostimulant and one of the most frequently used illicit drugs. Numerous genetic loci that influence complex traits, including alcohol abuse, have been discovered; however, genetic analyses for METH dependence remain limited. An increased histone deacetylase 3 (HDAC3) expression has been detected in Fos-positive neurons in the dorsomedial striatum following withdrawal after METH self-administration. Herein, we aimed to systematically investigate the contribution of HDAC3 to the vulnerability to METH dependence in a Han Chinese population.MethodsIn total, we recruited 1,221 patients with METH dependence and 2,328 age- and gender-matched controls. For genotyping, we selected 14 single nucleotide polymorphisms (SNPs) located within ± 3 kb regions of HDAC3. The associations between genotyped genetic polymorphisms and the vulnerability to METH dependence were examined by single marker- and haplotype-based methods using PLINK. The effects of expression quantitative trait loci (eQTLs) on targeted gene expressions were investigated using the Genotype-Tissue Expression (GTEx) database.ResultsThe SNP rs14251 was identified as a significant association signal (χ2 = 9.84, P = 0.0017). An increased risk of METH dependence was associated with the A allele (minor allele) of rs14251 [odds ratio (95% CI) = 1.25 (1.09–1.43)]. The results of in silico analyses suggested that SNP rs14251 could be a potential eQTL signal for FCHSD1, PCDHGB6, and RELL2, but not for HDAC3, in various human tissues.ConclusionWe demonstrated that genetic polymorphism rs14251 located at 5q31.3 was significantly associated with the vulnerability to METH dependence in Han Chinese population.

目标甲基苯丙胺（METH）是一种中枢神经系统兴奋剂，也是最为广泛使用的非法药物之一。众多影响复杂性状的遗传位点，包括酒精滥用，已被发现；然而，针对METH依赖性的遗传分析仍显有限。在METH自我给药后的戒断期，背内侧纹状体中Fos阳性神经元表现出组蛋白去乙酰化酶3（HDAC3）表达的增加。本研究旨在系统性地探究HDAC3对汉族人群METH依赖性易感性的贡献。方法部分，我们招募了1,221名METH依赖症患者和2,328名年龄及性别匹配的健康对照者。针对基因分型，我们选取了位于HDAC3±3 kb区域内的14个单核苷酸多态性（SNPs）。利用PLINK软件，通过单标记和单倍型方法考察了基因型遗传多态性与METH依赖性易感性之间的关联。通过基因型-组织表达（GTEx）数据库，研究了表达数量性状基因座（eQTLs）对目标基因表达的影响。结果部分，我们发现SNP rs14251是一个显著的关联信号（χ2 = 9.84，P = 0.0017）。与rs14251的A等位基因（小等位基因）相关的METH依赖性风险增加[比值比（95%置信区间）= 1.25（1.09–1.43）]。计算机模拟分析结果提示，SNP rs14251可能成为FCHSD1、PCDHGB6和RELL2在不同人类组织中的潜在eQTL信号，但并非HDAC3。结论部分，我们证实了位于5q31.3的遗传多态性rs14251与汉族人群METH依赖性易感性的显著关联。