title: Identification of a new susceptibility variant for multiple sclerosis in OAS1 by population genetics analysis.
abstract: Contrasting results have been reported concerning the association of a splice-site polymorphism (rs10774671) in OAS1 with multiple sclerosis (MS). We analysed two OAS1 regions encompassing alternatively spliced exons. While the region carrying the splice-site variant is neutrally evolving, a signature of long-standing balancing selection was observed across an alternative exon 7. Analysis of variants in this exon identified an insertion/deletion polymorphism (rs11352835, A/-) that originates predicted products with distinct C termini. This variant is located along the major branch of the haplotype genealogy, suggesting that it may represent the selection target. A case/control study for MS indicated that rs11352835 is associated with disease susceptibility (for an allelic model with the deleted allele predisposing to MS, OR 1.27, 95% CI 1.072-1.513, p = 0.010). No association was found between rs10774671 and MS. As the two SNPs are in linkage disequilibrium in Europeans, the previously reported association between rs10774671 and MS susceptibility might be driven by rs11352835, possibly explaining the contrasting results previously observed for the splice-site polymorphism. Thus, we describe a novel susceptibility variant for MS in OAS1 and show that population genetic analyses can be instrumental to the identification of selection targets and, consequently, of functional polymorphisms with an effect on phenotypic traits.
authors: Bioinformatic Lab, Scientific Institute IRCCS E. Medea, Via don L. Monza 20, 23842, Bosisio Parini, LC, Italy.
authors: Rachele
authors: R
authors: Cagliani
authors: Matteo
authors: M
authors: Fumagalli
authors: Franca R
authors: FR
authors: Guerini
authors: Stefania
authors: S
authors: Riva
authors: Daniela
authors: D
authors: Galimberti
authors: Giacomo P
authors: GP
authors: Comi
authors: Cristina
authors: C
authors: Agliardi
authors: Elio
authors: E
authors: Scarpini
authors: Uberto
authors: U
authors: Pozzoli
authors: Diego
authors: D
authors: Forni
authors: Domenico
authors: D
authors: Caputo
authors: Rosanna
authors: R
authors: Asselta
authors: Mara
authors: M
authors: Biasin
authors: Elvezia M
authors: EM
authors: Paraboschi
authors: Nereo
authors: N
authors: Bresolin
authors: Mario
authors: M
authors: Clerici
authors: Manuela
authors: M
authors: Sironi
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics*; D000328:Adult; D016022:Case-Control Studies; D004247:DNA / Q000032:analysis / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008297:Male; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D004247:DNA; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase