(PA-273) Insights into Ubiquitination-Associated Genes in Multiple Myeloma: A Multi-Omics Mendelian Randomization Study

Introduction: Multiple myeloma (MM), a malignant plasma cell disorder with age-related incidence, presents bone pain, anemia, and renal dysfunction. Current therapies (chemotherapy, proteasome inhibitors) face challenges like resistance, toxicity, and cost. Ubiquitination influences MM progression via protein degradation and DNA repair, yet its specific roles in drug resistance remain unclear. This Mendelian randomization study integrates multi-omics (eQTLs/mQTLs/pQTLs) and GWAS data to identify causal ubiquitination-related genes and methylation/expression regulators using SMR analysis. By uncovering pathogenic mechanisms and therapeutic targets, this framework aims to address treatment limitations and advance precision strategies for MM.

Methods: This study used multi-omics Mendelian randomization (MR) approach to explore the causal associations between ubiquitination-related genes and MM. The analysis integrated genome-wide association study (GWAS) data from the UK Biobank (discovery dataset) and FinnGen R11(validation dataset), along with blood methylation quantitative trait loci (mQTLs), expression QTLs (eQTLs) and protein QTLs (pQTLs). The summary data-based MR (SMR) method and HEIDI test were employed to evaluate the associations and pleiotropy. Colocalization analysis identified shared genetic variants, and the integration of eQTLs, mQTLs, and pQTLs data explored the causal associations between DNA methylation, gene expression, and protein abundance.

Results:

This study integrated MM GWAS with ubiquitination-associated blood mQTLs, eQTLs, and pQTLs to identify causal genetic-epigenetic interactions. SMR analysis revealed 70 MM-associated methylation sites (48 genes), including SPOP with opposing effects: cg14245135 increased risk (OR=1.37) and cg05551217 decreased it (OR=0.53). Nine ubiquitination-related genes (e.g., EED, SPOP, UBAP1) showed divergent MM associations via eQTLs, while pQTLs implicated STC1 (protective) and TNFAIP3 (risk). Multi-omics integration highlighted LTN1, SPOP, and UBAP1, where methylation (e.g., SPOP’s cg14245135/cg05551217) bidirectionally regulated gene expression and MM risk. Hypermethylation at LTN1 sites suppressed expression, elevating risk, whereas UBAP1 hypomethylation reduced expression, increasing susceptibility. Colocalization supported most methylation effects (except LTN1’s cg24692254) and UBAP1 expression, though FinnGen validation failed for eQTL/pQTL findings. Epigenetic modulation of ubiquitination-related genes—particularly SPOP’s dual methylation effects—underscores complex gene-environment interactions in MM pathogenesis. 

Conclusions: Our findings highlight the potential causal roles of ubiquitination-related genes, particularly LTN1, SPOP, and UBAP1, in MM pathogenesis. Future study should focus on validating these genes to develop targeted therapeutic strategies.