Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's disease and Parkinson's disease using polygenic risk scores and Mendelian randomization.
Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's disease and Parkinson's disease using polygenic risk scores and Mendelian randomization.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
San Francisco, US · Author affiliation
Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, California, USA.Location evidence
New York City, US · Author affiliation
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.Location evidence
Bethesda, US · Author affiliation
Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, Maryland, USA.Location evidence
US · Author affiliation · country only
DataTecnica LLC, Washington, District of Columbia, USA.Location evidence
Los Angeles, US · Author affiliation
Alzheimer's Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.Location evidence
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Original abstract
INTRODUCTION: Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with Alzheimer's disease (AD) and Parkinson's disease (PD). We integrated genetic correlation, polygenic risk scores (PRSs), 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 (GWASs) distort these causal estimates. METHODS: Using GWASs of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the Alzheimer's Disease Genetics Consortium (N = 27,383), and applied MR methods including latent heritable confounder-MR (LHC-MR). RESULTS: Across the four mtDNAcn GWASs, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRSs 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.