Uncovering Putative Causal Non-coding RNAs in Acute and Chronic Myeloid Leukemia: A Genome-Wide Mendelian...

Although non-coding RNAs (ncRNAs) have often been implicated in various cancers, their causal roles in acute (AML) and chronic myeloid leukemia (CML) remain unclear. Here, we conducted a genome-wide two-sample Mendelian randomization (MR) study to investigate the causal effects of a comprehensive set of ncRNAs on AML and CML.

We used summary statistics of blood expression quantitative trait loci (eQTL) from the eQTLGen consortium (31,684 European participants) as exposure data. Genome-wide association study summary statistics from the FinnGen study (AML, 322 cases; CML, 303 cases) and UK Biobank (UKBB) (AML, 318 cases; CML, 153 cases) served as outcome data. The generalized inverse-variance weighted (GIVW) method was used as the primary MR method. Two additional MR methods (generalized MR-Egger and weighted median), sensitivity analyses, and the HEIDI test were further employed to support our findings.

Upregulated HCG22 and RP11-42I10.1 were causally linked to increased AML risk, while the GMDS-AS1 locus was positively associated with increased CML risk. We highlight these ncRNAs for their consistent significance across all three MR methods, with no evidence of bias in sensitivity analyses (F-test, Cochran's Q-test, MR-Egger intercept, MR-PRESSO global test) and no indication of confounding from the HEIDI test. These findings were primarily discovered in FinnGen (FDRGIVW < 0.05), their significance was validated in UKBB (pGIVW < 0.05). Upon validation with an independent linkage disequilibrium reference panel, they remained robust.

This study provides evidence of causal relationships between ncRNAs and the subtypes of AML and CML, notably highlighting HCG22 and RP11-42I10.1 in AML and the GMDS-AS1 locus in CML.