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.

Fig. 1

Schematic representation of the OAS1 gene region and alternative transcripts. Transcribed regions are shown in grey and the corresponding protein products are reported. The direction of transcription is indicated by the arrows. Alternatively spliced exons are shown in darker grey. The two regions we resequenced (OAS1 _r1 and OAS1 _r2) are indicated by the hatched lines. The asterisk shows the position of rs11352835; rs10774671 is circled. The LD (r ²) plot refers to CEU and data were derived from HapMap

Fig. 2

Network analysis for OAS1 _r2. Each node represents a different haplotype, with the size of the circle proportional to frequency. Nucleotide differences between haplotypes are indicated on the branches of the network. The position of rs11352835 (A insertion/deletion in the alternative exon 7) is shown. Circles are colour-coded according to population (green YRI, blue CEU, red EAS). The most recent common ancestor (MRCA) is also shown (black circle). The relative position of mutations along a branch is arbitrary

Fig. 3

GENETREE analysis for OAS1 _r2. Mutations are represented as black dots and named for their physical position along the region. The absolute frequency of each haplotype is also reported. Note that mutation numbering does not correspond to that reported in Fig. 2