title: Association between the ACCN1 gene and multiple sclerosis in Central East Sardinia.
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.
authors.affiliation: Dipartimento di Scienze Sanitarie Applicate e Psicocomportamentali, Università di Pavia, Pavia, Italy. luisa.bernardinelli@mrc-bsu.cam.ac.uk
authors.forename: Luisa
authors.initials: L
authors.lastname: Bernardinelli
authors.forename: Salvatore Bruno
authors.initials: SB
authors.lastname: Murgia
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Bitti
authors.forename: Luisa
authors.initials: L
authors.lastname: Foco
authors.forename: Raffaela
authors.initials: R
authors.lastname: Ferrai
authors.forename: Luigina
authors.initials: L
authors.lastname: Musu
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.forename: Roberta
authors.initials: R
authors.lastname: Pastorino
authors.forename: Valeria
authors.initials: V
authors.lastname: Saddi
authors.forename: Anna
authors.initials: A
authors.lastname: Ticca
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Piras
authors.forename: David Roxbee
authors.initials: DR
authors.lastname: Cox
authors.forename: Carlo
authors.initials: C
authors.lastname: Berzuini
mesh_terms: D062565:Acid Sensing Ion Channels; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D062626:Degenerin Sodium Channels; D053503:Epithelial Sodium Channels / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007558:Italy; D009103:Multiple Sclerosis / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C568424:ASIC2 protein, human; D062565:Acid Sensing Ion Channels; D062626:Degenerin Sodium Channels; D053503:Epithelial Sodium Channels; D009419:Nerve Tissue Proteins