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

Abstract

ABSTRACTThe role of common genetic variation 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. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2309 cases and 2814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based 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). ASSET identified an increased risk forde novoAML and MDS (OR=1.38, 95% CI, 1.26-1.51, Pmeta=2.8×10-12) in patients carrying the T allele at rs12203592 inInterferon Regulatory Factor 4(IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increasedIRF4gene expression is associated with increased risk ofde novoAML and MDS (OR=3.90, 95% CI, 2.36-6.44, Pmeta=1.0×10-7). The identification ofIRF4by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.