Data from: Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence

BACKGROUND: Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants. OBJECTIVE: To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), Catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients. METHODS: 303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs): rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also provide a multivariate model for the associations among them implying Bayesian networks in Bayesian multilevel analysis. FINDINGS AND CONCLUSIONS: In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, -521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the -521 C/T (rs1800955) polymorphism in the promoter.研究背景：海洛因依赖是一种具有复杂遗传基础的致残性精神障碍。由于多巴胺能系统在大脑奖赏机制中发挥关键作用，而多数成瘾性药物均会直接或间接靶向作用于该系统，因此本研究聚焦于多巴胺能基因变异的效应及其相互作用。研究目的：探讨匈牙利人群中多巴胺D2受体（dopamine D2 receptor, DRD2）、含锚蛋白重复序列与激酶结构域1（ankyrin repeat and kinase domain containing 1, ANKK1）、多巴胺D4受体（dopamine D4 receptor, DRD4）、儿茶酚-O-甲基转移酶（Catechol-O-methyl transferase, COMT）以及多巴胺转运体（dopamine transporter, SLC6A3）基因的等位基因变异与海洛因依赖之间的潜在关联。研究方法：本研究对303名海洛因依赖受试者与555名健康对照者的7个单核苷酸多态性（single nucleotide polymorphism, SNP）位点进行基因分型，具体包括：COMT基因的rs4680、DRD2基因的rs1079597与rs1800498、ANKK1基因的rs1800497，以及DRD4基因的rs1800955、rs936462与rs747302。同时对4个可变数目串联重复序列（variable number of tandem repeats, VNTR）位点进行基因分型：DRD4基因第3外显子的120bp重复序列与48bp VNTR，以及SLC6A3基因的40bp VNTR与内含子8 VNTR。此外，本研究构建了用于分析基因间关联的多变量模型，该模型基于贝叶斯多层分析中的贝叶斯网络（Bayesian networks）。研究结果与结论：单标记分析结果显示，TaqIA（rs1800497）与TaqIB（rs1079597）变异与海洛因依赖存在显著关联。此外，DRD4基因的-521 C/T单核苷酸多态性（rs1800955）呈现名义关联，其C等位基因可能具有保护作用。经邦费罗尼（Bonferroni）校正后，TaqIB位点仍具有统计学显著性，提示该位点的次要等位基因（A等位基因）是海洛因依赖遗传背景中的风险因素。额外开展的多标记分析结果与单标记分析结果一致，但该方法揭示了DRD4基因启动子区多态性位点rs936462的间接效应，且该效应通过启动子区的-521 C/T（rs1800955）多态性介导。