Exploring Causal Relationships Between Epigenetic Age and Neurodegenerative Disease
Researchers can use the strategy of Mendelian randomization to attempt to explore causation in human epidemiological data, provided that data includes information on gene variants associated with the outcomes of interest. Here, this approach is used to gain some insight into the direction of causation in the relationship between epigenetic age acceleration, an epigenetic age greater than chronological age, and the incidence of neurodegenerative conditions such as Alzheimer's disease.
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, intrinsic epigenetic age acceleration (IEAA), and HannumAge, (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6,618 to 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 (inverse-variance-weighted, IVW beta = -0.309). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10). 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.