Abstract
Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 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 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 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 catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.
Highlights
Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4)
Multiple sclerosis (OMIM 126200) is an inflammatory demyelinating disorder of the central nervous system that is a common cause of chronic neurological disability.1,2. It has its greatest prevalence amongst individuals of Northern European ancestry3 and is moderately heritable,4 with a sibling relative recurrence risk of ~ 6.3.5 Aside from the early success in demonstrating the important effects exerted by variants in the Human Leukocyte Antigen (HLA) genes from the Major Histocompatibility Complex (MHC),6 there was little progress in unravelling the genetic architecture underlying multiple sclerosis susceptibility prior to the advent of genome-wide association studies (GWAS)
The striking overlap in the genetic architecture underlying susceptibility to autoimmune diseases9,10,12,13 prompted the collaborative construction of the “ImmunoChip”, an efficient genotyping platform designed to deeply interrogate 184 non-MHC loci with genome-wide significant associations to at least one autoimmune disease and provide lighter coverage of other genomic regions with suggestive evidence of association
Summary
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