Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's and Parkinson's disease using Polygenic Risk
Aadrita Chatterjee1, Brian Alvarez2, Rakshya U Sharma1
1Department of Psychiatry and Behavioral Sciences, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA, USA Department of Psychiatry and Behavioral Sciences, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA, USA.
Introduction:
Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with AD and PD. We integrate genetic correlation, Polygenic Risk Scores (PRS), and Mendelian Randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWAS) may distort these causal estimates.
Methods:
Using GWAS of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the AD Genetics Consortium (N=27,383), and applied MR methods including Latent Heritable Confounder MR (LHC-MR).
Results:
Across the four mtDNAcn GWAS, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRS analysis showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk.
Discussion:
Higher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect.
Insights
Higher mitochondrial DNA copy number (mtDNAcn) is linked to a reduced risk of Alzheimer's disease (AD) and Parkinson's disease (PD). This study clarifies the causal relationship between mtDNAcn and neurodegenerative disease risk.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Mitochondrial DNA copy number (mtDNAcn) is a key indicator of mitochondrial health.
- The causal link between mtDNAcn and neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear.
- Genetic factors influencing mtDNAcn may impact disease risk.
Purpose of the Study:
- To investigate the causal relationship between mtDNAcn and the risk of AD and PD.
- To assess the influence of mtDNAcn on AD and PD susceptibility.
- To evaluate potential biases in genome-wide association studies (GWAS) of mtDNAcn.
Main Methods:
- Utilized genome-wide association studies (GWAS) for four mtDNAcn measures, AD, AD/dementia, and PD.
- Performed genetic correlation analyses and generated Polygenic Risk Scores (PRS).
- Applied Mendelian Randomization (MR) methods, including Latent Heritable Confounder MR (LHC-MR).
Main Results:
- One mtDNAcn GWAS consistently associated with AD/dementia and PD.
- Genetic correlation and PRS analyses revealed negative correlations between mtDNAcn and disease risk.
- Mendelian Randomization indicated that increased mtDNAcn causally reduces the risk of AD/dementia and PD.
Conclusions:
- Elevated blood-based mtDNAcn is causally associated with a decreased risk of AD/dementia and PD.
- Evidence for a bidirectional relationship between mtDNAcn and these neurodegenerative diseases is limited.
- mtDNAcn represents a potential protective factor against AD and PD.
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