Human Genetics

, Volume 131, Issue 1, pp 87–97 | Cite as

Identification of a new susceptibility variant for multiple sclerosis in OAS1 by population genetics analysis

  • Rachele Cagliani
  • Matteo Fumagalli
  • Franca R. Guerini
  • Stefania Riva
  • Daniela Galimberti
  • Giacomo P. Comi
  • Cristina Agliardi
  • Elio Scarpini
  • Uberto Pozzoli
  • Diego Forni
  • Domenico Caputo
  • Rosanna Asselta
  • Mara Biasin
  • Elvezia M. Paraboschi
  • Nereo Bresolin
  • Mario Clerici
  • Manuela Sironi
Original Investigation

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.

Supplementary material

439_2011_1053_MOESM1_ESM.doc (696 kb)
Supplementary Tables (DOC 696 kb)
439_2011_1053_MOESM2_ESM.doc (72 kb)
Supplementary Figures (DOC 71 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Rachele Cagliani
    • 1
  • Matteo Fumagalli
    • 1
  • Franca R. Guerini
    • 2
  • Stefania Riva
    • 1
  • Daniela Galimberti
    • 3
  • Giacomo P. Comi
    • 3
  • Cristina Agliardi
    • 2
  • Elio Scarpini
    • 3
  • Uberto Pozzoli
    • 1
  • Diego Forni
    • 1
  • Domenico Caputo
    • 4
  • Rosanna Asselta
    • 5
  • Mara Biasin
    • 6
  • Elvezia M. Paraboschi
    • 5
  • Nereo Bresolin
    • 1
    • 3
  • Mario Clerici
    • 7
    • 8
  • Manuela Sironi
    • 1
  1. 1.Bioinformatic LabScientific Institute IRCCS E. MedeaBosisio PariniItaly
  2. 2.Laboratory of Molecular Medicine and Biotechnologies, Don C. Gnocchi Foundation ONLUSIRCCSMilanItaly
  3. 3.Department of Neurological Sciences, Dino Ferrari Centre, Fondazione Ca’ Granda IRCCS Ospedale Maggiore PoliclinicoUniversity of MilanMilanItaly
  4. 4.Multiple Sclerosis Unit, Don C. Gnocchi Foundation ONLUSIRCCSMilanItaly
  5. 5.Dipartimento di Biologia e Genetica per le Scienze MedicheUniversità degli Studi di MilanoMilanItaly
  6. 6.DISC LITA VialbaUniversity of MilanoMilanItaly
  7. 7.Department of Biomedical Sciences and Technologies LITA SegrateUniversity of MilanMilanItaly
  8. 8.Fondazione Don C. GnocchiIRCCSMilanItaly

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