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.

Keywords: causal relationship; epigenetic age acceleration; epigenetic clock; longevity; neurodegenerative disorders; shared genetic etology.

FIGURE 1

Study overview. An overview of this study's data sources and main analyses. AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; cML‐MA, constrained maximum likelihood and model average‐based MR method; GTEx, Genotype‐tissue Expression Project; IVW, inverse variance weighted; LBD, Lewy body dementia; MR, Mendelian randomization; MR‐PRESSO, Mendelian Randomization Pleiotropy‐RESidual Sum and Outlier; MS, multiple sclerosis; MsigDB, Molecular signatures Database; PD, Parkinson's disease.

FIGURE 2

Results of inverse variance‐weighted Mendelian randomization analysis. Inverse variance‐weighted Mendelian randomization estimates for genetically predicted effects of Alzheimer's disease on epigenetic age accelerations (a) and multivariate longevity (b). IEAA, Intrinsic HorvathAge. MR result of each neurodegenerative disease subgroup was pooled by fixed effect meta‐analysis. *Indicated suggestive significance. ***Indicated significance.

FIGURE 3

Cross‐trait enrichment between Alzheimer's disease, epigenetic aging, and human longevity. Quantile‐quantile (Q‐Q) plots illustrate cross‐trait enrichment between AD and GrimAge age acceleration (a), as well as AD and exceptional longevity (b). Conditional Q‐Q plots of nominal versus empirical $-{\log }_{10}p$, in which p represents the p values corrected for inflation, in primary phenotypes below the GWAS significance threshold of p < 5 × 10⁻⁸ as a function of significance of association with the second phenotypes, at p < 0.10, p < 0.01, p < 0.001. The dashed lines indicate the null hypothesis. The blue lines indicate all SNPs.

FIGURE 4

Shared loci between Alzheimer's disease, epigenetic aging, and human longevity. Common genetic variants jointly associated with AD and GrimAge age acceleration (a), and AD and exceptional longevity (b) at conjFDR < 0.05. Manhattan plots showing the −log10 transformed conjFDR values for each SNP on the y‐axis and chromosomal positions along the x‐axis. The dotted horizontal lines represent the threshold for significant shared associations (conjFDR < 0.05, i.e., $-\log 10\left(\text{conjFDR}\right)>1.3$). Independent lead SNPs are circled in black. More detailed information about the identified loci, please see Tables S8 and S10.