Integrative genomic deconvolution of rheumatoid arthritis GWAS loci into gene and cell type associations

Abstract

BackgroundAlthough genome-wide association studies (GWAS) have identified over 100 genetic loci associated with rheumatoid arthritis (RA), our ability to translate these results into disease understanding and novel therapeutics is limited. Most RA GWAS loci reside outside of protein-coding regions and likely affect distal transcriptional enhancers. Furthermore, GWAS do not identify the cell types where the associated causal gene functions. Thus, mapping the transcriptional regulatory roles of GWAS hits and the relevant cell types will lead to better understanding of RA pathogenesis.ResultsWe combine the whole-genome sequences and blood transcription profiles of 377 RA patients and identify over 6000 unique genes with expression quantitative trait loci (eQTLs). We demonstrate the quality of the identified eQTLs through comparison to non-RA individuals. We integrate the eQTLs with immune cell epigenome maps, RA GWAS risk loci, and adjustment for linkage disequilibrium to propose target genes of immune cell enhancers that overlap RA risk loci. We examine 20 immune cell epigenomes and perform a focused analysis on primary monocytes, B cells, and T cells.ConclusionsWe highlight cell-specific gene associations with relevance to RA pathogenesis including the identification of FCGR2B in B cells as possessing both intragenic and enhancer regulatory GWAS hits. We show that our RA patient cohort derived eQTL network is more informative for studying RA than that from a healthy cohort. While not experimentally validated here, the reported eQTLs and cell type-specific RA risk associations can prioritize future experiments with the goal of elucidating the regulatory mechanisms behind genetic risk associations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0948-6) contains supplementary material, which is available to authorized users.

An Analysis of the Association between Epilepsy-Related Genes and Vertigo in the Polish Population

“…The promoter regions of the MMP1 and MMP8 genes have reduced methylation in the omental arteries of preeclamptic women compared with those of normal pregnant women. Most association studies (both gene-based and genome-wide) show that identifying mechanisms underlying intronic variants is complex [Walsh et al, 2016]. Therefore, a possible regulatory role of rs1939012 and rs1783901 needs to be further elucidated by transcriptome and other gene expression analyses.…”

Understanding Human Autoimmunity and Autoinflammation Through Transcriptomics

“…eQTL analyses have been conducted in SLE (200, 201), T1D (200), RA (201–203), IBD (201), celiac disease (201), MS (201), Sjögren syndrome (204), ankylosing spondylitis (205), and AAV (206), among others. A large eQTL meta-analysis in more than 8,000 peripheral blood samples identified both cis - and trans -eQTLs associated with disease processes in SLE and T1D (200).…”

“…Combining these results with previous GWAS further identified new eQTLs at 34 IBD-associated loci. Another approach mapped eQTLs to population-specific enhancer regions in RA, identifying different patterns of SNP–enhancer gene connections between monocytes and B and T cells (203). Mapping eQTLs to discrete leukocyte populations in active and remission phases of autoimmunity may therefore help uncover disease-, disease activity–, and population-specific eQTLs, in addition to highlighting leukocyte subsets involved in pathogenesis.…”

Personalized medicine in rheumatology

“…The abundance of a gene transcript can be directly modified by genetic variants in regulatory elements which may modulate gene expression of local genes (cis-expression quantitative trait loci (eQTL), likely acting on the same chromosome) or genes at a distance on non-contiguous chromosomes (trans-eQTL) [18, 27]. eQTLs are a powerful tool to connect polymorphisms of unknown function whose expression levels are associated with a complex trait because of pleiotropy [28, 29]. …”