Abstract
The 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 (2,309 cases and 2,814 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 for de novo AML and MDS (OR = 1.38, 95% CI, 1.26-1.51, Pmeta = 2.8 × 10–12) in patients carrying the T allele at s12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. 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 = 1.0 × 10–7). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.
Highlights
Genome-wide association studies (GWAS) have been successful at identifying risk loci in several hematologic malignancies, including acute myeloid leukemia (AML; Knight et al, 2009; Lv et al, 2017; Walker et al, 2019)
We performed the first large scale AML and myelodysplastic syndromes (MDS) genome-wide association studies (GWAS) in a URD-BMT population providing evidence of novel pleiotropic risk loci associated with increased susceptibility to AML and MDS
We identified an association between the T allele at rs12203592 in Interferon Regulatory Factor 4 (IRF4) and an increased risk for the development of de novo AML, de novo MDS and therapy-related MDS (t-MDS) in patients who had undergone URD-BMT compared to healthy donor controls
Summary
Genome-wide association studies (GWAS) have been successful at identifying risk loci in several hematologic malignancies, including acute myeloid leukemia (AML; Knight et al, 2009; Lv et al, 2017; Walker et al, 2019). To systematically test the association of genetically predicted gene expression with disease risk, we performed a transcriptome wide association study (TWAS; Gamazon et al, 2015; Gusev et al, 2016). The predicted gene expression levels were tested for association with AML and MDS The use of both a GWAS and TWAS in the DISCOVeRY-BMT study population allowed us to identify AML and MDS associations with IRF4, a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation, and has been previously identified in GWAS of BCM (Law et al, 2017)
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