Genomic regions associated with multiple sclerosis are active in B cells.

Giulio Disanto,Julia M Morahan,Antonio J Berlanga-Taylor,Geir Kjetil Sandve,Gavin Giovannoni,Ruth Dobson,Sreeram V Ramagopalan,Christoph Kleinschnitz

doi:10.1371/journal.pone.0032281

Abstract

More than 50 genomic regions have now been shown to influence the risk of multiple sclerosis (MS). However, the mechanisms of action, and the cell types in which these associated variants act at the molecular level remain largely unknown. This is especially true for associated regions containing no known genes. Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated regions and single nucleotide polymorphisms (SNPs) and 2) chromatin profiling in B cells as well as three additional cell types thought to be unrelated to MS (hepatocytes, fibroblasts and keratinocytes). Genomic intervals and SNPs were tested for overlap using the Genomic Hyperbrowser. We found that MS associated regions are significantly enriched in strong enhancer, active promoter and strong transcribed regions (p = 0.00005) and that this overlap is significantly higher in B cells than control cells. In addition, MS associated SNPs also land in active promoter (p = 0.00005) and enhancer regions more than expected by chance (strong enhancer p = 0.0006; weak enhancer p = 0.00005). These results confirm the important role of the immune system and specifically B cells in MS and suggest that MS risk variants exert a gene regulatory role. Previous studies assessing MS risk variants in T cells may be missing important effects in B cells. Similar analyses in other immunological cell types relevant to MS and functional studies are necessary to fully elucidate how genes contribute to MS pathogenesis.

Highlights

Multiple sclerosis (MS) is a complex immune mediated disorder of the central nervous system which arises from a combination of genetic and environmental factors and their interactions [1]
Data acquisition Genetic variants associated with MS risk were obtained from the recent genome wide association study (GWAS) performed by the International Multiple Sclerosis Genetics Consortium (IMSGC) and the Wellcome Trust Case Control Consortium 2 (WTCCC2) [2]
In order to assess whether the significant global overlap was homogeneously distributed across the genome or resulted from highly enriched regions, the same analysis was performed on a local scale by dividing the whole genome into chromosome arms

Summary

Introduction

Multiple sclerosis (MS) is a complex immune mediated disorder of the central nervous system which arises from a combination of genetic and environmental factors and their interactions [1]. A recent genome wide association study (GWAS) involving more than nine thousand MS patients found evidence for association of MS with 57 genomic regions [2]. There remains limited understanding as to how these variants are involved in MS development. T cells have traditionally been thought to mediate MS pathophysiology, attention to the role of B cells is increasing [3,4]. The regulation of genes can be just as important as the proteins they encode. Regulatory elements in the genome are much harder to identify than protein-coding genes because they lack distinguishing sequence signatures. Many regulatory elements function only in certain cell types and conditions [7]

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