Multiple sclerosis (MS) is a common autoimmune demyelinating disorder of the central nervous system characterized by a complex etiology that includes a strong genetic component. The overall goal of this proposal is to identify the major genetic components involved in MS susceptibility and pathogenesis. We recently completed a 10 cM whole genomic screen and identified 19 discrete chromosomal regions that harbor potential MS genes. Our follow-up data also indicate that: a) sporadic and familial MS have a similar underlying immunogenetic basis; b) the genetic effect of the MHC region on MS is stronger than previously thought, at least in families; c) stratification by DR2 alleles supports the concept that HS is a heterogeneous disorder, and; d) a previously unknown area of interest may exist between the class I MHC region and the telomeric hemochromatosis locus. These results, which have profound implications towards a clarification of the underlying biology of MS, form the basis of this application to further explore the genetic basis of MS by use of multiple molecular, statistical, and neuroimaging approaches. In the first aim, the extended MHC region at chromosome 6p21 will be studied by saturation genotyping and analysis of candidate genes mapped to this area. A multi-analytical linkage strategy, using lod score, affected-relative-pair and sib-pair tests of linkages to these new markers will be applied to family data. Association studies will be performed for family data using the transmission/disequilibrium test (TDT) and sib-TDT. In the second aim, candidate genes in the vicinity of the promising chromosomal regions identified in the 10cM genomic screen will be tested for mutations and informative polymorphisms, particularly single nucleotide polymorphisms (SNPs), next to or within a candidate gene. Data will be stratified based upon DR2 status to detect both independent (e.g.in DR2-families) and interactive (DR2+ families) actions between MHC and other susceptibility or modifier loci. Finally, in Aim 3, clinical and paraclinical variables will be stratified by MHC types to address the question of heterogeneity in MS and the correlation between different phenotypes and genotypes. Key to the success of these studies will be the acquisition of a large dataset of singleton families, and the standardization of rigorous and consistent methods to use relevant clinical and neuroimaging (MRI) features of MS as stratifying variables for genetic analyses.