A Conserved Sequence Approach for MS Association Studies

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DESCRIPTION (provided by applicant): Genomic linkage screens have served as the workhorse of genetic studies for complex diseases over the past decade. Despite the success of these screens in identifying regions of interest for complex diseases, follow-up of linkage regions with candidate gene approaches have largely failed to identify causative loci. The goal of the current proposal is to employ a novel approach to investigate genetic association on the scale of a linkage peak for a complex genetic disease. Using multiple sclerosis (MS) as a model, this approach focuses on selection of SNP markers located in multi-species conserved sequences identified using new comparative sequence analysis tools. As for many complex genetic diseases, researchers have conducted numerous genomic screens in an attempt to identify regions potentially harboring MS loci. Thorough follow-up of all candidate genes in all regions of linkage for MS has proven to be prohibitive in terms of both time and cost, and has ultimately failed to identify susceptibility genes outside of the major histocompatibility complex. It is likely that these candidate gene studies for MS have been hampered by the incomplete identification and characterization of genes or regulatory elements that are directly related to disease pathophysiology. This research proposal aims to formulate a systematic approach to expedite the follow-up of positional candidate regions identified through linkage studies and apply this approach to a genomic region that demonstrates significant linkage to MS. We hypothesize that by focusing on SNPs located in evolutionarily conserved regions, we can increase the likelihood of detecting variants that are associated with disease. The specific aims of the proposed project are to: 1.) Prioritize SNP markers for an MS association study on chromosome 1q43 based on conservation between human, mouse, rat, and chick genome sequences; 2.) Measure association between a dense population of SNPs located in conserved regions of interest on chromosome 1q43 and a dataset of ~200 multiplex and ~600 simplex MS families. The novel approach for follow-up of linkage studies proposed in this study will increase the likelihood of successfully identifying a genetic factor in the 1q43 region and will potentially demonstrate a paradigm that expedites the search for genes in MS and other complex diseases.