Shared Genetic Links Between Rheumatoid Arthritis and White Blood Cell Traits Revealed

Rheumatoid arthritis is a heritable autoimmune disease, but the extent to which its genetics overlap with the genes that shape white blood cell counts has remained poorly defined. A new study published in BMC Immunology set out to map these shared immunogenetic mechanisms by integrating large-scale genome-wide association study data from both European and East Asian populations.

The researchers first used linkage disequilibrium score regression to estimate genetic correlations between rheumatoid arthritis and white blood cell traits. This analysis identified significant genetic correlations between the disease and eosinophil count in people of European ancestry, and with lymphocyte and neutrophil counts in East Asian populations. The population-specific pattern suggests that the shared genetic architecture between immune cell traits and rheumatoid arthritis susceptibility differs across ancestries.

To probe whether these correlations reflect causal relationships, the team applied bidirectional Mendelian randomization in population-stratified analyses. This approach supported associations between white blood cell traits and rheumatoid arthritis susceptibility, with evidence running in both directions between the traits and disease risk.

Beyond correlations at the genome-wide level, the researchers used multi-trait analysis of GWAS to pinpoint specific pleiotropic loci that influence both rheumatoid arthritis and leukocyte traits. This identified multiple genome-wide significant shared signals, including putatively novel ones. One signal stood out: at the 2q13 locus, the variant rs11123201 showed a shared regional signal and a directionally concordant association with rheumatoid arthritis in the Million Veteran Program, an independent cohort that corroborated the finding.

To connect the genetic signal to biology, the team examined gene expression in affected tissue. Bulk microarray analysis confirmed that BCL2L11, a gene located in the 2q13 region, is expressed at lower levels in rheumatoid arthritis synovial tissue than in healthy synovial tissue, a difference that remained significant after correction for the false discovery rate. Donor-aware single-cell analysis then showed broadly concordant expression patterns for the gene across immune-cell subsets, supporting the robustness of the expression difference.

Together, the findings delineate population-stratified pleiotropic genetic relationships between rheumatoid arthritis and white blood cell traits and prioritize BCL2L11 at 2q13 for future functional work. The study’s strength lies in its cross-ancestry design and its combination of statistical genetics with tissue-level expression evidence, while its conclusions rest on association-level analyses that will require experimental follow-up to establish biological causality.

Subject of Research: Shared immunogenetic mechanisms between rheumatoid arthritis and white blood cell traits

Article Title: Uncovering shared immunogenetic mechanisms linking rheumatoid arthritis and leukocyte traits

Article References: Zhang, Q., Wang, X., Song, Y., Liu, Z., Jiang, Y., Wu, Q., Zhang, M., Ye, W., Yu, H., Ullah, K., Mu, W., Chang, X., Wang, C., & Hakonarson, H. (2026). Uncovering shared immunogenetic mechanisms linking rheumatoid arthritis and leukocyte traits. BMC Immunology. https://doi.org/10.1186/s12865-026-00919-4

Image Credits: AI Generated

DOI: 10.1186/s12865-026-00919-4

Keywords: rheumatoid arthritis, white blood cells, genetics, GWAS, Mendelian randomization, BCL2L11, 2q13 locus, genetic correlation, pleiotropy, immunogenetics, synovial tissue, single-cell analysis