Refining the Genetic Basis of the Dopamine Hypothesis of Schizophrenia

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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.