Whole genome association screen in multiple sclerosis
On behalf of the International Multiple Sclerosis Genetics Consortium (IMSGC).
Available evidence suggests that familial clustering in multiple sclerosis is almost exclusively due to shared genetic factors. Early candidate gene studies quickly identified the importance of the Human Leukocyte Antigen (HLA) DR15 haplotype but subsequent whole genome linkage screens have failed to conclusively identify any other susceptibility factors. Results from the most recent high-density linkage screen indicate that non-HLA loci exert only modest effects individually and will require testing for association in large datasets if they are to be identified with any statistical confidence.
Results from the human genome variation project have confirmed that linkage disequilibrium (LD), the correlation between closely mapped loci, is a highly variable but common feature of the human genome. One often considered consequence of this LD is the possibility to effectively screen very nearly all the common variation in the human genome by typing just a proportion of these variants, especially if the typed variants are carefully chosen to capture as much of the available variation as possible (e.g. tagging). The technology required to undertake such “indirect” whole genome association screening is now a reality. In our indirect association screen for multiple sclerosis the International Multiple Sclerosis Genetics Consortium (IMSGC) is genotyping the Affymetrix 500k chip in 1000 trio families (an affected individual and both parents). Based on data from the International HapMap project we anticipate that this chip will allow us to effectively interrogate at least 70% of the common variation in the human genome. Pilot study data has revealed highly accurate and efficient genotyping with 94% of the first 238,304 markers in the project genotyping in more than 80% of samples and a Mendelian error rates of just 0.3% per meiosis. The results from this screen will be presented.