Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets

Abstract

Although genome-wide association studies have implicated many individual loci in complex diseases, identifying the exact causal alleles and the cell types within which they act remains greatly challenging. To ultimately understand disease mechanism, researchers must carefully conceive functional studies in relevant pathogenic cell types to demonstrate the cellular impact of disease-associated genetic variants. This challenge is highlighted in autoimmune diseases, such as rheumatoid arthritis, where any of a broad range of immunological cell types might potentially be impacted by genetic variation to cause disease. To this end, we developed a statistical approach to identify potentially pathogenic cell types in autoimmune diseases by using a gene-expression data set of 223 murine-sorted immune cells from the Immunological Genome Consortium. We found enrichment of transitional B cell genes in systemic lupus erythematosus (p = 5.9 × 10(-6)) and epithelial-associated stimulated dendritic cell genes in Crohn disease (p = 1.6 × 10(-5)). Finally, we demonstrated enrichment of CD4+ effector memory T cell genes within rheumatoid arthritis loci (p < 10(-6)). To further validate the role of CD4+ effector memory T cells within rheumatoid arthritis, we identified 436 loci that were not yet known to be associated with the disease but that had a statistically suggestive association in a recent genome-wide association study (GWAS) meta-analysis (p(GWAS) < 0.001). Even among these putative loci, we noted a significant enrichment for genes specifically expressed in CD4+ effector memory T cells (p = 1.25 × 10(-4)). These cell types are primary candidates for future functional studies to reveal the role of risk alleles in autoimmunity. Our approach has application in other phenotypes, outside of autoimmunity, where many loci have been discovered and high-quality cell-type-specific gene expression is available.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

“…For example, there is an over-representation of SLE loci expressed selectively in B cells; RA-associated loci are preferentially expressed in CD4 þ effector T memory cells; epithelial-associated stimulated dendritic cell genes in Crohn disease; and monocyte-specific eQTLs among neurodegenerative disease variants. 77,78 Abnormal inflammatory response and activation of microglial cells are linked with the development of AD and other neurodegenerative diseases. The WBC-associated gene CD33 is among the inflammation-related AD risk loci identified by GWASs.…”

Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies

“…More precise cell subset definitions of the active enhancer landscape have provided additional insight into autoimmune disease pathogensis 95 . The greatest enrichment of GWAS signals is observed within active transcriptional regions for a variety of CD4 + effector T cells (for example, T H 17, T H 1, T H 2) for numerous autoimmune diseases including multiple sclerosis, celiac disease, primary biliary cirrhosis, type 1 diabetes, rheumatoid arthritis and inflammatory bowel disease.…”

The Therapeutic Potential of Epigenetics in Autoimmune Diseases

“…In the case of multiple sclerosis, the higher concordance rates include 7.5 years of median follow-up of the unaffected twins differences. It should be noted, however, that genomic susceptibility remains a crucial element in determining disease susceptibility, as well illustrated by the recent data from GWAS in SLE [101][102][103][104], systemic sclerosis (SSc) [105,106], and other autoimmune diseases [107][108][109][110] in which a geoepidemiological gradient applies. As an example, a significant increase in the prevalence of SLE cases was reported in a neighborhood exposed to oil field waste, with possible synergistic effects of pollutants, including pristine, mercury and phytane, mercury, and other exposures [44].…”