# Integrating Bidirectional Mendelian Randomization with Multi-Omics Reveals Causal Serum Metabolites and Novel Metabolic Drivers of Multiple Myeloma

## TL;DR

This study identifies specific serum metabolites and genes that causally influence multiple myeloma risk, offering new insights into potential treatments.

## Contribution

The study integrates bidirectional MR with multi-omics to reveal causal serum metabolites and novel metabolic drivers of multiple myeloma.

## Key findings

- Eight serum metabolites showed protective inverse correlations with multiple myeloma risk.
- Thirteen serum metabolites were found to enhance multiple myeloma risk.
- Key pathways like valine/leucine/isoleucine biosynthesis and biotin metabolism were identified as pivotal in MM development.

## Abstract

Multiple myeloma (MM) is a clonal plasma cell neoplasm characterized by autonomous immunoglobulin overproduction. Despite associations between serum metabolites and MM, causal mechanisms remain unclear. Here, we employed bidirectional Mendelian randomization (MR) using 452 serum metabolites to elucidate causal associations with MM risk. The inverse variance-weighted (IVW) method was prioritized, complemented by MR-Egger and weighted median (WM) analyses to address horizontal pleiotropy. Sensitivity analyses—including Cochran’s Q test, MR-Egger intercept evaluation, and leave-one-out (LOO) robustness checks—confirmed result stability. Pathway enrichment was performed using MetaboAnalyst 6.0. RNA-seq data were integrated to identify transcriptional regulators and signaling pathways mediating serum metabolite-driven MM. Among 21 metabolites significantly associated with MM, 8 exhibited protective inverse correlations, while 13 showed risk-enhancing effects. Sensitivity analyses further confirmed the validity of the observed relationships, while bidirectional MR confirmed no reverse causality. Pathway enrichment highlighted valine/leucine/isoleucine biosynthesis and biotin metabolism as pivotal pathways. Integrating transcriptomic data revealed 11 overlapping genes enriched in metal ion transmembrane transporter activity and glycosaminoglycan biosynthesis—chondroitin sulfate/dermatan sulfate. This study established a causal relationship between specific serum metabolites and MM and revealed that key genes may affect the development of MM through metabolic-epigenetic crosstalk, providing preliminary insights into potential therapeutic targets.