title: Integrative genomic deconvolution of rheumatoid arthritis GWAS loci into gene and cell type associations.
abstract: BACKGROUND
  Although 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Immunology, Janssen Research and Development, LLC., 1400 McKean Rd., Spring House, PA, 19477, USA.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Walsh
authors.affiliation: Discovery Sciences, Janssen Research and Development, LLC., 3210 Merryfield Row, San Diego, CA, 92101, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Whitaker
authors.affiliation: Immunology, Janssen Research and Development, LLC., 1400 McKean Rd., Spring House, PA, 19477, USA.
authors.forename: C Chris
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Immunology, Janssen Research and Development, LLC., 1400 McKean Rd., Spring House, PA, 19477, USA.
authors.forename: Yauheniya
authors.initials: Y
authors.lastname: Cherkas
authors.affiliation: Immunology, Janssen Research and Development, LLC., 1400 McKean Rd., Spring House, PA, 19477, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Lamberth
authors.affiliation: Immunology, Janssen Research and Development, LLC., 1400 McKean Rd., Spring House, PA, 19477, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Brodmerkel
authors.affiliation: Immunology, Janssen Research and Development, LLC., 1400 McKean Rd., Spring House, PA, 19477, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Curran
authors.affiliation: Immunology, Janssen Research and Development, LLC., 1400 McKean Rd., Spring House, PA, 19477, USA. rdobrin@its.jnj.com.
authors.forename: Radu
authors.initials: R
authors.lastname: Dobrin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D044127:Epigenesis, Genetic; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008214:Lymphocytes / Q000145:classification / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D040641:Quantitative Trait Loci; D017452:Receptors, IgG / Q000235:genetics
chemical_list: C499173:FCGR2B protein, human; D017452:Receptors, IgG
keywords: Epigenomics; Expression quantitative trait loci (eQTLs); Genome-wide association studies (GWAS); Rheumatoid arthritis