Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene

Abstract

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

Figure 1

Population-Specific Association for the STAT3 rs744166 A Allele The rs744166 A allele that tags a putative MS protective haplotype associated to MS and shows consistent reduced risk in all studied populations with available genotypes. The results are presented here by study set. Each line represents one study set showing the name of the set, A allele frequencies for cases and controls, ORs, p value for association, and graphic illustration of the odds ratio (square, size relative to study set size) with the 95% confidence intervals for the odds ratio (thin lines).

Figure 2

Description of the Associated LD Region in STAT3 The associated SNP and haplotypes are in a 54 kb LD block covering the beginning and immediate 5′ region of the STAT3 gene. The associated rs744166 SNP is marked with a red arrow, and the other two SNPs, rs6503695 and rs957970, used in the haplotype analysis are marked with yellow arrows. The SNP marked with the blue arrow (rs2293152) was listed among the 100 top SNPs suggestively associated to MS in a previous meta-analysis.