Refining the Genetic Basis of the Dopamine Hypothesis of Schizophrenia

完善精神分裂症多巴胺假说的遗传学基础

• 批准号: 7276381
• 负责人: MICHAEL E TALKOWSKI
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-13 至 2009-12-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276381
• 关键词: Accounting; Affect; Alternative Splicing; Bioinformatics; Biological Assay; Brain; Catechol O-Methyltransferase; Cell Line; Clinical; Custom; DNA; DNA Sequence; Data; Databases; Development; Disease; Dopamine; Economic Burden; Etiology; Evaluation; Family; Gene Expression; Genes; Genetic; Genetic Epistasis; Genetic Models; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genomics; Genotype; Haplotypes; Healthcare Systems; Heritability; Hyperactive behavior; In Vitro; India; Individual; Investigation; Maps; Methylation; Mission; Molecular; Nature; Nuclear Family; Parents; Pathogenesis; Pathway interactions; Population; Predisposition; Public Health; RNA Splicing; Research; Resolution; Resources; Risk; Role; Sampling; Schizophrenia; Signal Transduction; Statistically Significant; Techniques; Testing; Therapeutic; Transcriptional Regulation; Variant; base; case control; cohort; design; dopamine D3 receptor; dopamine transporter; gene interaction; genetic association; genetic risk factor; mRNA Expression; neurotransmission; novel; promoter; size

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.

描述(申请人提供)：精神分裂症(SZ)是一种常见的致残性疾病，发病机制不明。目前尚无根治SZ的方法。这种疾病的遗传病因已被广泛接受，但遗传模式尚不确定。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基因。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，暗示脑DA功能亢进。先前测试DA假说的遗传关联研究一直没有定论，可能是因为设计缺陷和动力不足。DA基因之间的上位性交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评估高功率样品中更大比例的代表性变异成为可能。因此，所需的资源可用于挑战先前的结论，并重新评估DA途径中的关键基因，以支持或反对疾病发病机制的作用。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，即多巴胺转运体(SLC6A3)、多巴胺D3受体(DRD3)和儿茶酚-O-甲基转移酶(COMT)。我们的分析发现了具有代表性的Tag SNPs之间显著的主效应和交互作用。在两个队列中进行的复制研究是有希望的。然而，产生统计意义的确切负债变量及其功能相关性仍然不清楚。这些信号的解决可能会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中所有常见的遗传变异进行详尽的评估，以确定准确的易感基因座及其功能影响。 综合评估基于基因的关联，并改进合理的易感基因座列表，1a。通过对DNA池进行重新测序，确定所有在种群中常见的基因组变异(MAP&GT；2-5%)。IB/C.在四个队列(n=7,390)中对新的SNPs进行基因分型，以确定相关基因、基因座和相互作用。通过体外研究，确定相关变异的功能效应和上位性相互作用。测试所有可能的易感基因座对转录调控、剪接变异和基因表达的影响，库。使用定制开发的SLC6A3表达特定细胞系评估新的上位性相互作用。 公共卫生标志：精神分裂症对受影响的人是毁灭性的，治疗是姑息的。深圳给美国医疗体系带来的经济负担是巨大的(2002年为620亿美元)。我们的分析可能会对SZ的发病机制有更好的理解，为合理治疗的发展铺平道路。