The classic method of finding disease genes -linkage mapping - works well for rare, monogenic disorders. However, linkage scans have failed to find the genes for many common and genetically complex diseases such as multiple sclerosis (MS). While the state-of-the-art method of finding disease genes - the haplotype-based association study - has greater statistical power than linkage studies, it requires the genotyping of hundreds of thousands of markers. We hypothesize that an admixture scan can be used to screen for MS genes about 100 times more efficiently than a haplotype-based study. An admixture scan has the potential to rapidly identify disease regions for the subset of diseases with different prevalence rates in two populations. MS is an excellent candidate disease for an admixture scan. The risk for MS in African-Americans may derive largely from high-risk European alleles; as a result, we can search for MS genes simply by looking for islands enriched in European ancestry in the genomes of African-American MS patients that are, for the most part, West African in origin.
Aim 1 : Building a high-resolution admixture map of the human genome. Admixture mapping has only become conceivable within the past six months, with the identification of large numbers of sites in the genome with known allele frequencies in different human populations.
Our first Aim will be to generate a validated map of about 3,300 Single Nucleotide Polymorphisms (SNPs) spaced on average every 1.5 Mb of the genome.
Aim 2 : Carrying out a whole-genome admixture scan for multiple sclerosis. We will genotype the entire map in 1,500 African-American subjects with MS. 1) We will analyze the data using computer programs that calculate, at every point in the genome, the probability that the observed proportion of European ancestry is greater than the expected (background) value. 2) At loci where associations to disease are identified, we will triple the density of markers to refine the boundaries of the locus.
Aim 3 : Identifying the risk haplotypes. The admixture scan will demarcate regions that contain risk alleles for MS. A haplotype-based association study within the African-American study population will be necessary to identify the risk haplotvpe and eventually the risk allele.
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