GENETICS OF GENE EXPRESSION IN PRIMARY IMMUNE CELLS IDENTIFIES CELL-SPECIFIC MASTER REGULATORS AND ROLES OF HLA ALLELES

Trans-acting genetic variants play a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B-cells we identify novel, predominantly cell-specific, cis- and trans-eQTL (expression quantitative trait loci). These include multi-locus trans-associations to LYZ in monocytes and to KLF4 in B-cells. Additionally, we observe B-cell specific trans-association of rs11171739 at 12q13.2, a known autoimmune disease locus, to IP6K2 (p(B-cell)=5.8×10(−15)), PRIC285 (p(B-cell)=3.0×10(−10)) and an upstream region of CDKN1A (p(B-cell)=2×10(−52); p(monocyte)=1.8×10(−4)), suggesting roles for cell cycle regulation and PPARγ signaling in disease pathogenesis. We also find specific HLA alleles forming trans-association with the expression of AOAH and ARHGAP24 in monocytes but not in B-cells. In summary, we demonstrate that mapping gene expression in defined primary cell populations identifies new cell-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.