Mov Disord

. 2025 Jan 22.

doi: 10.1002/mds.30123. Online ahead of print.

Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases

Zheyi Wang ^{1 2}, Yize Sun ³, Zetai Bai ^{1 2}, Mei Li ^{1 2}, Deyuan Kong ^{1 2}, Guanzhao Wu ^{1 2}

Affiliations Expand

• PMID: 39838927

DOI: 10.1002/mds.30123

Abstract

Background: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.

Methods: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.

Results: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.

Conclusions: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.



Looks like the energy supply has a causal role in many diseases.