Refining the Genetic Basis of the Dopamine Hypothesis of Schizophrenia

描述（申请人提供）：精神分裂症（SZ）是一种常见的致残疾病，发病机制尚不清楚。对于SZ没有治愈的治疗方法。这种疾病的遗传病因已被广泛接受，但遗传方式尚不确定。遗传模型表明，风险最好的解释是具有可能上位性的多个贡献位点。经过几十年的临床观察和功能研究，得出了SZ的多巴胺（DA）假说，暗示大脑DA功能亢进。先前测试DA假设的遗传关联研究没有得出结论，可能是因为设计缺陷和功率不足。DA基因之间的上位相互作用也没有被考虑。分子技术和生物信息学的显著进步现在使得在高功率样品中评估更大比例的代表性变异成为可能。因此，有必要的资源来挑战先前的结论，并重新评估DA通路中的关键基因在疾病发病机制中的作用。我们对18个DA基因进行了这样的研究，发现了三个有趣的调节DA神经传递的靶点，即多巴胺转运蛋白（SLC6A3）、多巴胺D3受体（DRD3）和儿茶酚- o -甲基转移酶（COMT）。我们的分析发现了显著的主效应和代表性标签snp之间的相互作用。正在进行的两个队列的重复研究很有希望。然而，产生统计意义的确切责任变体及其功能相关性仍然模糊不清。对这些信号的分析可以在理解这种疾病的遗传病因方面取得重大进展。因此，我们建议对这些基因组区域的所有常见遗传变异进行详尽的评估，以确定精确的责任位点及其功能影响。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a common, disabling illness with unkown pathogenesis. There is no curative treatment for SZ. A genetic etiology for the disorder is widely accepted, but the mode of inheritance is uncertain. Genetic models suggest risk is best explained by multiple contributing loci with possible epistasis. Clinical observations and functional research over several decades have derived the dopamine (DA) hypothesis of SZ, implicating hyperactivity of brain DA function. Prior genetic association studies that tested the DA hypothesis have been inconclusive, possibly because of deficient design and inadequate power. Epistatic interactions between DA genes have also not been considered. Remarkable advances in molecular techniques and bioinformatics now make it feasible to evaluate a much greater proportion of representative variations in highly powered samples. Hence, the required resources are available to challenge previous conclusions and re-evaluate critical genes in the DA pathway for, or against, a role in disease pathogenesis. We undertook such an effort for 18 DA genes and found three intriguing targets that modulate DA neurotransmission, namely the dopamine transporter (SLC6A3), the dopamine D3 receptor (DRD3), and catechol-O-methyltransferase (COMT). Our analyses detected significant main effects and interactions between representative tag SNPs. Ongoing replicate studies in two cohorts are promising. However, the exact liability variants generating the statistical significance, and their functional relevance, remains obscure. Resolution of these signals could yield significant advances in understanding the genetic etiology of the disorder. We therefore propose an exhaustive evaluation of all common genetic variation in these genomic regions to determine the precise liability loci and their functional impact. I. Comprehensively evaluate gene based associations and refine the list of plausible susceptibility loci, la. Identify all genomic variation common in the population (MAP > 2-5%) by re-sequencing DNA pools. Ib/c. Genotype novel SNPs in four cohorts (n = 7,390) to determine associated genes, loci, and interactions. II. Determine the functional effects of associated variants, and epistatic interactions, through in vitro studies. lla.Test all plausible liability loci for effects on transcription regulation, splice variation, and gene expression, lib.Evaluate novel epistatic interactions using custom developed SLC6A3 expression specific cell lines. Public Health Singificance: Schizophrenia is devastating to those affected and treatment is palliative. The economic burden of SZ on the US healthcare system is enormous ($62 billion in 2002). Our analyses may enable a better understanding of SZ pathogenesis, paving the way for development of rational therapeutics.