Supplementary Material for: Dopaminergic Pathway Gene Polymorphisms and Genetic Susceptibility to Schizophrenia among North Indians

<i>Objective:</i> Understanding the etiology and pathogenesis of schizophrenia has been difficult due to the complex inheritance patterns, genetic heterogeneity and varied multiple nonlinear interactions between genes. Several lines of evidence indicate the involvement of neurotransmitter dopamine in the pathophysiology of this disorder. To analyze such a possible role of dopaminergic pathway gene polymorphisms, we used a case-control approach. <i>Method:</i> We genotyped a total of 31 potential single nucleotide polymorphism/variable number of tandem repeat markers from 9 candidate genes including the dopamine receptors and metabolizing enzymes (synthesis and degradation) in 215 schizophrenia cases and 215 healthy controls from North India. <i>Results:</i> A nominally significant allelic association was observed in case of the catechol-O-methyltransferase rs362204 –/G (p = 0.028) marker whereas nominally significant genotypic associations were seen for tyrosine hydroxylase rs6356 A/G (p = 0.04) and dopamine β-hydroxylase rs1108580 A/G (p = 0.025) following the case-control approach. Several significant haplotypic associations were observed from dopamine β-hydroxylase, catechol-O-methyltransferase, and dopamine receptor D₂ genes. A significant interaction of tyrosine hydroxylase rs6356 A/G and catechol-O-methyltransferase rs362204 –/G markers was also observed following binary logistic regression analysis (p = 0.009). <i>Conclusions:</i> A contribution of dopaminergic pathway gene polymorphisms to schizophrenia seems possible in our sample set. However, considering the marginal levels of associations, interpopulation comparisons and replicate studies are warranted.

研究目的：由于精神分裂症存在复杂的遗传模式、遗传异质性以及基因间多样的多重非线性相互作用，解析其病因与发病机制一直颇具难度。多项研究证据表明，神经递质多巴胺（dopamine）参与了该疾病的病理生理过程。为探究多巴胺能（dopaminergic）通路基因多态性的潜在作用，我们采用了病例-对照（case-control）研究设计。
研究方法：我们对来自印度北部的215例精神分裂症患者与215例健康对照个体进行基因分型，共检测了9个候选基因中的31个潜在单核苷酸多态性（single nucleotide polymorphism, SNP）/可变数目串联重复序列（variable number of tandem repeat, VNTR）标记位点，所纳入的候选基因涵盖多巴胺受体及参与多巴胺合成与降解的代谢酶。
研究结果：经病例-对照分析后发现，儿茶酚-O-甲基转移酶（catechol-O-methyltransferase, COMT）rs362204 –/G标记位点呈现名义显著性等位基因关联（p = 0.028）；酪氨酸羟化酶（tyrosine hydroxylase, TH）rs6356 A/G（p = 0.04）与多巴胺β-羟化酶（dopamine β-hydroxylase, DBH）rs1108580 A/G（p = 0.025）则分别表现出名义显著性基因型关联。此外，我们在多巴胺β-羟化酶、儿茶酚-O-甲基转移酶及多巴胺D₂受体（dopamine receptor D₂, DRD₂）基因中检测到多个显著单倍型关联。经二元logistic回归分析验证，酪氨酸羟化酶rs6356 A/G与儿茶酚-O-甲基转移酶rs362204 –/G标记位点间存在显著交互作用（p = 0.009）。
研究结论：本研究队列数据提示，多巴胺能通路基因多态性可能对精神分裂症的发生存在一定贡献。但鉴于本次关联效应处于临界水平，未来仍需开展跨人群比较研究及重复验证实验。