Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Figure 1. Discovery phase results

Primary association analysis of 161,311 autosomal variants in the discovery phase (based on 14,498 cases and 24,091 healthy controls). The outer most track shows the numbered autosomal chromosomes. The second track indicates the gene closest to the most associated SNP meeting all replication criteria. Previously identified associations are indicated in grey. The third track indicates the physical position of the 184 fine-mapping intervals (green). The inner most track indicates −log(p) (two-sided) for each SNP (scaled from 0-12 which truncates the signal in several regions, see Supplementary Table 1). Additionally, contour lines are given at the a priori discovery(−log(p) = 4) and genome-wide significance (-log(p) = 7.3) thresholds. Orange indicates -log(p) ≥ 4 and < 7.3, while red indicates −log(p) ≥ 7.3. Details of the full discovery phase results can be found in ImmunoBase.

Figure 2. Bayesian fine-mapping within primary regions of association

a) Summary of the extent of fine-mapping across 66 regions in 9,617 healthy controls from the UK, showing the the physical extent of, the number of variants, and the number of genes spanned by the posterior 90% and 50% credible sets. b) Detail of fine-mapping in region of TNFSF14. Above the x-axis indicates the Bayes Factor summarizing evidence for association for the SNPs prior to conditioning (blue markers) while below the x-axis indicates the Bayes Factor after conditioning on the lead SNP (rs1077667). Mb=Megabases.