Enrichment of Genetic Variants for Rheumatoid Arthritis within T-Cell and NK-Cell Enhancer Regions.

Jan Freudenberg,Wentian Li,Peter Gregersen

doi:10.2119/molmed.2014.00252

Jan Freudenberg, Wentian Li + Show 1 more

Open Access

https://doi.org/10.2119/molmed.2014.00252

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Abstract

To identify disease-causative variants, we intersected the published results of a metaanalysis of genome-wide association studies (GWAS) for rheumatoid arthritis (RA) with the set of enhancer regions for 71 primary cell types that was provided by the FANTOM consortium. We first retrieved all single nucleotide polymorphisms (SNPs) that are associated (P < 5 × 10(8)) with RA in the GWAS meta-analysis and that are located in any of these enhancer regions. After excluding the major histocompatibility complex (MHC) region, we identified 50 such RA-associated SNPs that are located in enhancer regions. Enhancer sets from different cell types were then compared with each other for their number of RA-associated SNPs by permutation analysis. This analysis showed that RA-associated SNPs are preferentially located in enhancers from several immunological cell types. In particular, we see a strong relative enrichment in enhancer regions that are active in T cells (P < 0.001) and NK cells (P < 0.001). Several loci display multiple RA-associated SNPs in tight linkage disequilibrium that are located within the same or neighboring enhancers. These haplotypes may have a greater likelihood to influence enhancer activity than any SNP on its own. Taken together, these results support the hypothesis that RA-causative variants often act through altering the activity of immune cell enhancers. The enrichment in T-cell and NK-cell enhancer regions indicates that expression changes in these cell types are particularly relevant for the pathogenesis of RA. The specific SNPs that account for this enrichment can be used as a basis for focused genotype-phenotype studies of these cell types.

Highlights

Several genome-wide association studies (GWAS) have been undertaken to investigate the genetic basis of rheumatoid arthritis (RA) [1,2,3,4,5,6,7]
The implicated genes were further tested for their enrichment in molecular pathways. For many loci, it remains unclear which single nucleotide polymorphisms (SNPs) constitute the actual causal variants. We examine this question by combining the RA GWAS metaanalysis results with a set of enhancer regions for 71 primary cell types, which was recently pub
We found 50 RAassociated SNPs that fall into enhancer regions, which are distributed over 21 different gene loci

Summary

INTRODUCTION

Several genome-wide association studies (GWAS) have been undertaken to investigate the genetic basis of rheumatoid arthritis (RA) [1,2,3,4,5,6,7] These studies have been recently combined into a transcontinental metaanalysis [8], which most comprehensively evaluates the influence of common single nucleotide variants on RA susceptibility in populations with European and Asian ancestry. Given that susceptibility variants typically exert their effect through modifying gene expression [10], this large enhancer set can be highly valuable to search for causal variants in current GWAS results. Using this set of enhancer regions to interpret RA GWAS results can point to cell types where gene activity may be altered through RA susceptibility variants and that have important roles in RA pathogenesis

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DISCLOSURE