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 (P¼0.008, OR¼1.29; 95% CI¼1.08-1.54), rs11808092 (P¼0.048, OR¼1.19; 95% CI¼1.03-1.39) and rs6680578 (P¼0.0082, OR¼1.23; 95% CI¼1.07-1.41). 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 ¼1), 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.

Genome-wide CTCF distribution in vertebrates defines equivalent sites that aid the identification of disease-associated genes

“…The most probable causal variants of the association to multiple sclerosis (MS) have been located in the last intron of the EVI5 gene 24 . Thus, one or several CREs within this intron may be affected in the risk haplotypes.…”

“…Several GWAS found a set of MS-associated polymorphisms belonging to the same linkage disequilibrium block located in a region containing the GFI1 (growth factor-independent 1), EVI5 (ecotropic viral integration site 5), RPL5 (ribosomal proteinL5) and FAM69 (family with sequence similarity 69) 2122,23 . A fine mapping of this genomic region was performed pointing to polymorphisms located within the 17th intron of the EVI5 gene as the most probable causal variants of the association 24 . However, these findings did not clarify the functional role of this EVI5 risk region.…”

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

“…different genes in the locus were linked to the association signal [61–64]. In this locus, GWAS meta-analysis identified multiple statistically independent genome-wide effects, three of which were found under the same association peak.…”

Gfi1–cells and circuits: unraveling transcriptional networks of development and disease

“…These findings may have some relevance to human disease in that 21 SNPs within the GFI-EVI5-RPL5-FAM69A locus were associated with MS in 732 patients. One SNP in the 17 th intron of EVI5 had a significant association with disease (P=0.008, OR=1.29; 95% CI=1.08-1.54) [62]. Notably, MMLV insertion mutagenesis in the last intron of Evi5 activates murine Gfi1 expression [2], but it currently unclear whether the SNP functions similarly to affect human GFI1 expression.…”