IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

Abstract

A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 x 10(-9)), IL12A (P=3.08 x 10(-8)) and MPHOSPH9/CDK2AP1 (P=3.96 x 10(-8)). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P=1.18 x 10(-5)) and in peripheral blood mononuclear cells from subjects with MS (P=0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

Figure 1

Meta-analysis results within the RGS1 locus. The forest plot summarizes the results obtained for rs2760524 in the RGS1 locus for the replication phase, the discovery phase and the joint analysis. Summary ORs and respective 95% confidence intervals are calculated using the fixed-effect method. *These collections correspond to the ones used previously in the replication arm of the published genome-wide meta-analysis study.

Figure 2

Meta-analysis results within the IL12A locus. The forest plot summarizes the results obtained for rs4680534 in the IL12A locus for the replication phase, the discovery phase and the joint analysis. Summary ORs and respective 95% confidence intervals are calculated using the fixed-effect method. *These collections correspond to the ones used previously in the replication arm of the published genome-wide meta-analysis study.

Figure 3

Meta-analysis results within the MPHOSPH9/CDK2AP1 locus. The forest plot summarizes the results obtained for rs1790100 in the MPHOSPH9/CDK2AP1 locus for the replication phase, the discovery phase and the joint analysis. Summary ORs and respective 95% confidence intervals are calculated using the fixed-effect method. *These collections correspond to the ones used previously in the replication arm of the published genome-wide meta-analysis study.

Figure 4

CDK2AP1 RNA expression relative to rs1790100 in LCLs. The plot illustrates the distribution of CDK2AP1 expression values by genotype classes in LCLs from CEU. A reduced CDK2AP1 expression is observed in the presence of the rs1790100^G susceptibility allele. No rs1790100^GG homozygotes were observed in this sample of LCLs. A black line denotes the mean value for each category.

Figure 5

CDK2AP1 RNA expression relative to rs1790100 in PBMCs from subjects with relapsing–remitting MS and CIS. The plot illustrates the correlation between the lower CDK2AP1 RNA expression and the rs1790100^G susceptibility allele in RNA data obtained from mononuclear cells of subjects with relapsing–remitting MS and CIS. A black line denotes the location of the mean value for each category.