# Transcriptome Data Combined With Mendelian Randomization Analysis Identifies Key Genes Associated With Mitochondria and Programmed Cell Death in Intervertebral Disc Degeneration

## TL;DR

This study identifies key genes linked to mitochondrial dysfunction and cell death in intervertebral disc degeneration, offering potential targets for diagnosis and treatment.

## Contribution

The study combines transcriptome data and Mendelian randomization to identify causal genes in intervertebral disc degeneration.

## Key findings

- Six genes (BCKDHB, BID, TNFAIP6, VRK1, CAB39L, and TMTC1) were causally linked to intervertebral disc degeneration.
- BID, TNFAIP6, and TMTC1 were identified as key genes through machine learning and validation.
- A nomogram based on these genes was developed to predict IDD risk and improve clinical outcomes.

## Abstract

Intervertebral disc degeneration (IDD) is a major cause of cervical and lumbar diseases, significantly impacting patients' quality of life. Mitochondria and cell death have been implicated in IDD, but the key related genes remain unknown.

Differentially expressed genes (DEGs) between IDD and control samples were identified using GSE70362. Mitochondria‐related genes (MRGs) and programmed cell death‐related genes (PCDRGs) were intersected with DEGs to find DE‐MRGs and DE‐PCDRGs. Weighted gene co‐expression network analysis (WGCNA) identified key module genes, and the overlap with DEGs revealed candidate genes. Mendelian randomization (MR) analysis was used to determine genes causally linked to IDD. Machine learning and expression validation further refined key genes, which were then used to build a nomogram to predict IDD risk. Additionally, gene set enrichment analysis (GSEA), immune infiltration, and single‐cell analysis were performed.

A total of 515 DEGs were intersected with 224 key module genes, yielding 31 candidate genes. Six genes—BCKDHB, BID, TNFAIP6, VRK1, CAB39L, and TMTC1—showed a causal relationship with IDD. BID, TNFAIP6, and TMTC1 were further identified as key genes through machine learning and validation. A nomogram was developed based on these genes. GSEA revealed BID and TMTC1 were enriched in N‐glycan biosynthesis, TNFAIP6 and TMTC1 in aminoacyl tRNA biosynthesis, and BID and TMTC1 in ribosomal pathways. Activated dendritic cells, CD56dim natural killer cells, monocytes, and other immune cells were elevated in IDD, with TNFAIP6 strongly correlating with activated dendritic cells. Key genes were expressed at higher levels in degraded samples.

BID, TMTC1, and TNFAIP6 were identified as key genes linked to mitochondria and cell death in IDD, offering new insights for diagnosis and treatment.

This research underlines the translational potential of our findings in IDD, focusing on mitochondrial dysfunction and programmed cell death pathways. By pinpointing genes like BID, TMTC1, and TNFAIP6, our work offers promising targets for therapeutic development and diagnostic markers. The construction of predictive nomograms based on these genes could facilitate early diagnosis and personalized treatment strategies, significantly enhancing clinical outcomes for patients with IDD.