Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1

Abstract

Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 × 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.

Figure 1. Manhattan plot of Meta-Analysis of three GWAS datasets (Macarena, IMSGC/WT, GeneMSA).

Blue and red horizontal lines correspond to p values of 0.001 and 3.82×10-7 respectively.

Figure 2. Manhattan plot of Macarena GWAS.

Blue and red horizontal lines correspond to p values of 0.001 and 3.82×10-7 respectively.

Figure 3. Forest plot of Meta-analysis including the GWAS datasets (with GeneMSA included as three independent substudies), and the validation samples.

MAF: Minor Allele Frequency; US: United States; UK: United Kingdom; CH: Confoederatio Helvetica/Switzerland; HL: Holland.

Figure 4. Location of eQTLs of the 5p13.1 region and the SNPs associated to MS and Crohn diseases.

Image from the UCSC browser showing the chr5:39,840,547-40,924,217 (NCBI36/hg18) region. Vertical bars indicate the location of eQTLs and SNPs associated to Crohn or MS in different studies. eQTL PTGER4 are described by Zeller et al.; eQTL PTGER4 CEU are obtained from the correlation of PTGER4 expression in the CEU lymphoblastoid cell lines with the variants of the region; eQTL RPL37 are described by Stranger et al. and Dixon et al.; GWAS Crohn indicate the SNPs associated with the disease in different studies , , , ; GWAS MS indicate the SNPs associated with MS. LD plot performed with HapMap data from CEU population.