eQTL analysis of SLE B cells reveals functional genomic regulatory variation associated with autoimmunity 2253669

Introduction Systemic lupus erythematosus (SLE) is a complex and heterogenous autoimmune disease characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naïve cells. Ultimately the production and deposition of autoantibodies results in damage to multiple organ systems. Therefore, further defining the molecular drivers of extrafollicular B cell differentiation and antibody production is important to ultimately prevent and treat SLE. Genetic variants uncovered by GWAS studies only explain a portion of SLE heritability, with most polymorphisms located in non-coding regulatory elements. Expression Quantitative Trait Loci (eQTL) approaches functionally associate non-coding variant alleles with gene expression and cell type abundance changes to facilitate functional annotation of disease associated genetic variation and uncover alterations in gene regulatory networks that contribute to autoimmunity. However, no eQTL study to date has focused on SLE individuals of African ancestry (AFR), despite the higher disease prevalence and burden in this group. Methods Here, we integrated whole genome sequencing with scRNA-seq and scATAC-seq data on B cells obtained from 58 individuals with SLE, including 46 AFR, 7 European ancestry, and 5 healthy controls. Results We identified thousands of eQTLs where genetic variation correlated with changes in transcription in B cells. Analysis of B cell subsets including extrafollicular, naive, and switched memory cells, revealed eQTLs that were unique to distinct cell types and may promote the altered differentiation profile of B cells observed in SLE. Conclusion These analyses provide risk alleles and cellular pathways specific to SLE that may contribute to pathogenic B cell responses in autoimmunity. Funding Source NIH/NIAID P01 AI125180 and LRA GTSA 821168 Topic Categories Immune Mechanisms of Human Disease (HUM)