Replication of a GWAS signal near HLA-DQA2 with acute myeloid leukemia using a disease-only cohort and external population-based controls

ABSTRACT Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Its risk factors include rare and highly penetrant somatic mutations. Genome-wide association studies (GWAS) have also 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 = 1.88 1.21-2.93, P- value=0.005). The effect size of this association was stronger when we restricted the analyses to AML patients with NPM1 mutations (odds ratios >2.35). We found HLA- DOB to be the most significantly upregulated gene in Leucegene participants with the CN-AML protective A-allele at rs3916765. We further found that several HLA class II genes are also differentially expressed albeit at lower statistical significance. Our results confirm that a common genetic variant at the HLA locus associates with AML risk, providing new opportunities to improve disease prognosis and treatment.