Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis

Nat Genet. 2017 Jul;49(7):1120-1125. doi: 10.1038/ng.3885. Epub 2017 May 29.


Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4+ T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.

MeSH terms

  • Adult
  • Alleles
  • Arthritis, Rheumatoid / ethnology
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Asian Continental Ancestry Group / genetics
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Cytokines / genetics
  • Female
  • Gene Expression Profiling
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Immune System
  • Inflammation / genetics
  • Male
  • Models, Genetic
  • Multifactorial Inheritance*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Risk


  • Cytokines