Genome-wide association analyses identify variants inIRF4associated with acute myeloid leukemia and myelodysplastic syndrome susceptibility

Abstract

The role of common variants in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. These diseases may have a shared molecular basis and identifying germline loci associated with the risk for their development could be important. We performed AML and MDS genome-wide association studies (GWAS) in European Americans from the DISCOVeRY-BMT study population (2309 cases and 2814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNPbased analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). We identified an increased risk for de novo AML and MDS (OR=1.38, 95% CI, 1.26-1.51, Pmeta=2.8x10-12) in patients carrying the T allele at rs12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation.Variants in this gene are recognized to confer increased susceptibility to B-cell malignancies. Rs12203592 is <80 bp from an IRF4 transcription start site. Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS (OR=3.90, 95% CI, 2.36-6.44, Pmeta =1.0x10-7). The identification of IRF4 by both GWAS and TWAS contributes valuable insight into the limited evidence of common variants associated with AML and MDS susceptibility.