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Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity
Abstract
The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large‐scale genome‐wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618–482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse‐variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = −0.309, 95% CI: −0.38 to −0.24, p = 1.51E‐19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = −0.10, 95% CI: −0.188 to −0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.
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GWAS meta-analysis has revealed rs12691088's potential association with AD risk, and it appears to be a variant concurrently implicated in both epigenetic aging and AD risk.
“However, GWAS meta-analysis has revealed its potential association with AD risk, and it appears to be a variant concurrently implicated in both epigenetic aging and AD risk [81, 82].”
From Association of APOC1 with cortical atrophy during conversion to Alzheimer’s disease (2025) · cites this paper as [81]
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Sorted by citations
Association of APOC1 with cortical atrophy during conversion to Alzheimer’s disease
Oh, S., Kim, S., Kim, J. P., Seo, S. W., Park, B.-Y., & Park, H. (2025) · GeroScience · doi:10.1007/s11357-025-01695-6 · Cited by 4
Metadata
- Authors
- Guo, Y., Ma, G., Wang, Y., Lin, T., Hu, Y., & Zang, T.
- Affiliations
- School of Computer Science and Technology Harbin Institute of Technology Harbin China
- Beidahuang Industry Group General Hospital Harbin China
- ORCID
- Hu, Yang
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2024-09-19
- Volume
- 23
- Issue
- 11
- ISSN
- 1474-9718
- 1474-9726
- PMC
- PMC11561668
- Cited by
- 12
- References
- 11
- Language
- en
- Funders
- National Natural Science Foundation of China (62371161)
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