Abstract
Multiple genome screens have been performed to identify regions in linkage or association with Multiple Sclerosis (MS, OMIM 126200), but little overlap has been found among them. This may be, in part, due to a low statistical power to detect small genetic effects and to genetic heterogeneity within and among the studied populations. Motivated by these considerations, we studied a very special population, namely that of Nuoro, Sardinia, Italy. This is an isolated, old, and genetically homogeneous population with high prevalence of MS. Our study sample includes both nuclear families and unrelated cases and controls. A multi-stage study design was adopted. In the first stage, microsatellites were typed in the 17q11.2 region, previously independently found to be in linkage with MS. One significant association was found at microsatellite D17S798. Next, a bioinformatic screening of the region surrounding this marker highlighted an interesting candidate MS susceptibility gene: the Amiloride-sensitive Cation Channel Neuronal 1 (ACCN1) gene. In the second stage of the study, we resequenced the exons and the 3′ untranslated (UTR) region of ACCN1, and investigated the MS association of Single Nucleotide Polymorphisms (SNPs) identified in that region. For this purpose, we developed a method of analysis where complete, phase-solved, posterior-weighted haplotype assignments are imputed for each study individual from incomplete, multi-locus, genotyping data. The imputed assignments provide an input to a number of proposed procedures for testing association at a microsatellite level or of a sequence of SNPs. These include a Mantel-Haenszel type test based on expected frequencies of pseudocase/pseudocontrol haplotypes, as well as permutation based tests, including a combination of permutation and weighted logistic regression analysis. Application of these methods allowed us to find a significant association between MS and the SNP rs28936 located in the 3′ UTR segment of ACCN1 with p = 0.0004 (p = 0.002, after adjusting for multiple testing). This result is in tune with several recent experimental findings which suggest that ACCN1 may play an important role in the pathogenesis of MS.
Highlights
Multiple Sclerosis (MS) is a disabling disease of the central nervous system that affects young adults
The nuclei were subdivided according to type: 44 type-1 nuclei consisting of a proband and of his/her parents, plus occasionally the proband’s siblings; 22 type-2 nuclei consisting of the proband, of his/her spouse and of their children, and 12 type-3 nuclei consisting of a proband and of a corresponding unrelated control, matched by village of origin
The fact that the association signal found at D17S798 does not extend to the two microsatellites located about 2cM away from it is consistent with the fact that we found no evidence of linkage disequilibrium (LD) between the studied microsatellites
Summary
Multiple Sclerosis (MS) is a disabling disease of the central nervous system that affects young adults. Multiple genome screens have nominated over 70 regions in linkage or associated with MS. Apart from some replications of linkage in regions of Chromosomes 5 and 17 [3], little overlap outside MHC has been found among these studies. The statistical power to detect a modest effect may be low due to genetic heterogeneity within and among the studied populations. These considerations motivated our decision to study an isolated, genetically homogeneous, old population of the Italian province of Nuoro, Sardinia, where MS prevalence is 4–5 times as high as in the Italian mainland. The main objective of this paper is to report a genetic characterisation of MS in this very special population, and the discovery of an MS association with genes on Chromosome 17
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