Exploring mitochondrial genetic features in intervertebral disc degeneration through multi-omics integration...

Area of Science:

• Genetics
• Mitochondrial Biology
• Bioinformatics

Background:

• The genetic underpinnings of intervertebral disc degeneration (IVDD) are not fully understood, particularly the role of mitochondria.
• Investigating mitochondrial genetic factors is crucial for developing novel therapeutic strategies for IVDD.

Purpose of the Study:

• To explore the mitochondrial genetic basis of intervertebral disc degeneration (IVDD) using multi-omics Mendelian randomization (MR).
• To identify potential therapeutic targets and drugs for IVDD by integrating multi-omics data and genetic association studies.

Main Methods:

• Employed two-sample MR analysis integrating methylation, expression, protein abundance, and mitochondrial DNA quantitative trait loci from GWAS.
• Utilized FinnGen study and GWAS Catalog for genetic associations, with Steiger filtering and co-localization analysis for causal inference.
• Conducted Gene Ontology, KEGG, and drug prediction analyses to identify therapeutic targets, including molecular docking for HYDRONIDONE.

Main Results:

• Identified 23 genes associated with IVDD, with 5 genes (GATM, SLC25A13, ACADS, TSFM, ATP23) showing strong evidence.
• GATM demonstrated the most significant association, with higher GATM levels linked to reduced IVDD risk (OR: 0.934).
• Discovered 15 drugs targeting GATM and 11 drugs targeting ACADS, highlighting potential therapeutic avenues.

Conclusions:

• Multi-omics MR analysis successfully identified key mitochondrial genes involved in IVDD pathogenesis.
• GATM emerged as a promising therapeutic target for IVDD, supported by consistent multi-omics evidence and identified drug candidates.
• The study provides a foundation for developing targeted therapies for intervertebral disc degeneration by leveraging genetic and pharmacological insights.