Replication of a GWAS signal near HLA-DQA2 with AML using a disease-only cohort and external population-based controls Open Access

1. Common genetic variation in the HLA region modulates the risk of developing acute myeloid leukemia in cytogenetically normal patients.

2. This genetic risk is stronger in patients with NPM1 mutations.

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Genome-wide association studies (GWAS) have identified four common inherited variants associated with AML risk, but these findings have not yet been confirmed in many independent datasets. Here, we performed a replication study with 567 AML cases from the Leucegene cohort and 1,865 controls from the population-based cohort CARTaGENE (CaG). Because genotypes were generated using different technologies in the two datasets (e.g. low- vs. high-coverage whole-genome sequencing), we applied stringent quality-control filters to minimize type I errors. We showed using data reduction methods (e.g. principal component analysis [PCA] and uniform manifold approximation and projection [UMAP]) that our approach successfully integrated the Leucegene and CaG genetic data. We replicated the association between cytogenetically normal (CN)-AML and rs3916765, a variant located near HLA-DQA2 (odds ratio [95% confidence interval] = 1.96 [1.26-3.06], P-value=0.003). The effect size of this association was stronger when we restricted the analyses to AML patients with NPM1 mutations (odds ratios >2.25). We also found that rs3916765 is a whole-blood expression quantitative trait locus (eQTL) for HLA-DOB (P-value=1.05x10^-14) and HLA-DQA2 (P-value=2.23x10^-4). Our results confirm that a common genetic variant at the HLA locus associates with AML risk and the expression of HLA class II genes, providing new opportunities to improve disease prognosis and treatment.