Genetic regulation of B cell receptor signaling pathway: Insights from expression quantitative trait locus analysis using a mixed model

The B cell receptor (BCR) signaling pathway regulates non-immune cellular response through various pathways like MAPK, NF-kB, and PI3K-Akt. This study aimed to identify expression quantitative trait loci (eQTL) and their regulatory functions on BCR signaling pathway genes. A mixed model was employed to analyze eQTL using RNA expression levels in lymphoblastoid from 376 Europeans in the GEUVADIS dataset. In total, 266 SNPs, including 115 cis-acting SNPs, were found for association with transcription of 13 genes (P < 5 × 10⁻⁸), revealing 19 independent signals for five genes through linkage disequilibrium analysis. Functional analysis, aligning them with DNase sensitive sites, transcription factor binding sites, histone modification, promoters/enhancers, CpG islands, and ChIA-PET, identified regulatory variants targeting SYK, VAV2, and PLCG2. Notably, rs2562397 was validated as a SYK promoter variant, and rs694505, rs636667, and rs4889409 were confirmed as enhancer variants for VAV2 and PLCG2. Their allelic differences in gene expression were also confirmed using ENCODE ChIP-seq and Sei neural network prediction. Persistent differential expression of these genes by alleles might impact the adaptive immune system, vascular development, and/or relevant diseases that have been previously associated with other variants of the genes. Comprehensive genetic architecture studies of the BCR signaling pathway, along with experiments demonstrating related mechanisms, will greatly contribute to understanding the underlying mechanisms of relevant disease development and implementing precision medicine.