Mapping candidate non-MHC susceptibility regions to multiple sclerosis

Abstract

Understanding the genetic basis of multiple sclerosis (MS) remains a major challenge, despite decades of intensive research. In order to identify candidate non-MHC susceptibility regions to MS, the results of whole genome screens for linkage or association and follow-up studies in 18 different populations were superimposed together in a combined genomic map. Analysis of this map led to the prediction of at least 38 potential susceptibility regions, each showing linkage and/or association in several populations. Among these, 17 regions were the most reproducibly reported in these studies, thus representing top predicted candidates for MS. This non-formal approach to meta-analysis demonstrated the ability to verify results and retrieve lost information in an association study. Assessment of the map in a Northern Irish refined screen (n ¼ 415 cases, n ¼ 490 controls) revealed association in 15 regions (Po0.05), including 10 promising candidates on chromosomes 1p13, 2p13, 2q14, 3p23, 7q21, 13q14, 15q13, 17p13, 18q21 and 20p12 (Po0.0025). Seven of these regions were previously overlooked in the Northern Irish whole genome association study. Collating results from numerous studies, this draft map represents a tool that should facilitate the analysis of the genetic backgrounds of MS in many populations.

Genetics of primary progressive multiple sclerosis

“…In a follow-up study to a case-control study of MS susceptibility using microsatellite markers in a Northern Irish dataset (Heggarty et al, 2003;Abdeen et al, 2006) consisting of 348 RRMS (181 were classified as benign and 167 had aggressive MS) and 136 PPMS patients, genotype-phenotype correlations were assessed for the top 12 microsatellite markers associated with MS susceptibility identified by the genome-wide screen. Five of these markers retained statistical significance in this dataset after correction for multiple comparisons.…”

Multiple loci comprising immune-related genes regulate experimental neuroinflammation

“…[1][2][3] An influence from genes within the major histocompatibility complex (MHC) region is well established in MS and other inflammatory diseases, 4 and distinct regulation from non-MHC genes is only now emerging. 5 So far, only a few non-MHC genes have unambiguously been associated with MS, including IL2R and IL7R. [6][7][8] This is because of genetic heterogeneity, modest or weak effects of disease-predisposing genes, differences in environmental factors and use of cohorts of insufficient size.…”

Genomic Evaluation of Multiple Sclerosis

“…A recently published study combined the results of whole genome screens for linkage or association in 18 populations and superimposed them in a combined genomic map ( Abdeen et al, 2006 ). New experimental techniques and analytical methods, however, are trying to change this trend.…”

“…New experimental techniques and analytical methods, however, are trying to change this trend. The list of candidates includes genes involved in CNS development and regeneration (NTN1, NCAM1, ADAM22 and ADAMTS10) in addition to genes directly linked to infl ammation (TGFA, TGFBR, IL18 and IL10RA) ( Abdeen et al, 2006 ). The regions identifi ed by this meta-analysis were then verifi ed in a different set of samples ( Abdeen et al, 2006 ), leading to the identifi cation of several non-MHC candidate genes that modify the risk for MS.…”