Bone morphogenetic proteins, DNA methylation, and gut microbiota interaction in lumbar disc degeneration: A multi-omics Mendelian randomization study

Background: Lumbar disc degeneration (LDD) is a ubiquitous finding in low back pain. Many different etiology factors may explain the LDD process, such as bone morphogenetic proteins (BMPs), DNA methylation, and gut microbiota. Until recently the mechanisms underlying the LDD process have been elusive.

Methods: BMP-related genes were extracted from the GeneCards database. The LDD transcriptome dataset was obtained from the Gene Expression Omnibus. We used linear regression and meta-analysis to screen and integrate the differentially expressed genes associated with BMPs in LDD. Genome-wide association studies (GWASs) of LDD were from FinnGen and UKBB. The expression quantitative trait loci (eQTLs) and DNA methylation quantitative trait loci from the blood were identified via the summary data-based Mendelian randomization (SMR) method, and the possible blood BMP genes and their regulatory elements associated with the risk of LDD were prioritized. Intestinal eQTLs and fecal microbial QTLs (mbQTLs) were integrated, and the potential interactions between BMP gene expression in host intestinal tissue and the gut microbiota were revealed through SMR and colocalization analysis. The GWAS catalog (GCST90246169) was used to validate SMR results.

Results: A meta-analysis of five datasets revealed that 113 BMP genes were differentially expressed between LDD and control tissues. Seven genes were selected as candidate pathogenic genes of LDD via the three-step SMR method: CREB1, BMP6, PTCH1, GLI1, MEG3, GALNS, and NF1. SMR analysis also revealed five possible gut genes: HFE, MET, MAPK3, NPC1, and GDF5. The correlation between the gut microbiota and BMP gene expression in intestinal tissues was verified by eQTL-mbQTL colocalization.

Conclusion: This multi-omics study revealed that the BMP genes associated with LDD are regulated by DNA methylation. There are genetic differences between gut gene expression and the gut microbiota. These findings provide evidence for new therapeutic targets in the future.