Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis

Abstract

A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10), OR = 1.40). CBLB encodes a negative regulator of adaptive immune responses, and mice lacking the ortholog are prone to experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis.

Figure 1. Association and Linkage Disequilibrium patterns at the CBLB locus

A) Association of genotyped and imputed SNPs (-log₁₀ of the pvalue) around the CBLB gene. Comb diagrams indicate the location of successfully genotyped SNPs in Affymetrix 6.0 (filled diamonds) and of SNPs imputed (open circles) using haplotypes from 1000 Genomes as reference panel. The top SNP (rs9657904) is highlighted, and other SNPs are colored according to their degree of disequilibrium with this variant. The pvalue resulting from a joint analyses of samples used in the GWA scan and replication is annotated. CBLB transcript is indicated in the lower box, with ‘-’ indicating transcript’s direction. B) LD pattern in the Sardinian population.