Tag-SNP analysis of the GFI1-EVI5-RPL5-FAM69 risk locus for multiple sclerosis

Abstract

A recent genome-wide association study conducted by the International Multiple Sclerosis Genetic Consortium (IMSGC) identified, among others, a number of putative multiple sclerosis (MS) susceptibility variants at position 1p22. Twenty-one SNPs positively associated with MS were located at the GFI-EVI5-RPL5-FAM69A locus. In this study, we performed an analysis and fine mapping of this locus, genotyping eight Tag-SNPs in 732 MS patients and 974 controls from Spain. We observed an association with MS in three of eight Tag-SNPs: rs11804321 (P=0.008, OR=1.29; 95% CI=1.08-1.54), rs11808092 (P=0.048, OR=1.19; 95% CI=1.03-1.39) and rs6680578 (P=0.0082, OR=1.23; 95% CI=1.07-1.41). After correcting for multiple comparisons and using logistic regression analysis to test the addition of each SNP to the most associated SNPs, we observed that rs11804321 alone was sufficient to model the association. This Tag-SNP captures two SNPs in complete linkage disequilibrium (r(2)=1), both located within the 17th intron of the EVI5 gene. Our findings agree with the corresponding data of the recent IMSGC study and present new genetic evidence that points to EVI5 as a factor of susceptibility to MS.

Figure 1

The LD structure of Tag-SNPs at the GFI1-EVI5-RPL5-FAM69A locus and schematic illustration of the genes in the locus with the positions in chromosome 1 (Ch1). Pairwise r² values are shown for the Spanish population.

Figure 2

Summary effect estimate for SNPs rs6680578 (upper panel) and rs11164838 (lower panel) using information from four different studies: IMSGC (combined analysis of 1540 family trios and replicated in 2322 cases and 5418 controls), CANADIAN (Canadian Collaborative Project on the Genetic Susceptibility to MS performed on 756 families, which included 1318 individuals with definite MS and 1507 of their unaffected first-degree relatives), AUSTRALIAN (cohort of 1134 cases and 1265 controls), SPANISH, (this study consisted of 732 patients with clinically defined MS and 974 healthy controls). Individual effect estimates reported by the authors and their confidence intervals have been used. A random effects model was used when heterogeneity was observed (http://cran.r-project.org/web/packages/rmeta/index.html). The odds ratio (OR) estimate of each study is marked with a square, which is also indicated in the figure. The size of the square represents the weight that the corresponding study exerts in the meta-analysis. Estimated heterogeneity variance for rs6680578=0 (P=0.395), and for rs11164838=0.0071 (P=0.025).