Dissecting the Shared Genetic Architecture Between Alzheimer’s Disease and Frailty: A Cross-Trait Meta-Analyses of Genome-Wide Association Studies

Authors

Xiangning Chen
Yimei Lu
Joan Manuel Cue
Mira V Han
Vishwajit L Nimgaonkar
Daniel R Weinberger
Shizhong Han
Zhongming Zhao
Jingchun Chen

Publication Date

2-5-2025

Journal

Schizophrenia

Abstract

Introduction: Frailty is the most common medical condition affecting the aging population, and its prevalence increases in the population aged 65 or more. Frailty is commonly diagnosed using the frailty index (FI) or frailty phenotype (FP) assessments. Observational studies have indicated the association of frailty with Alzheimer’s disease (AD). However, the shared genetic and biological mechanism of these comorbidity has not been studied.

Methods: To assess the genetic relationship between AD and frailty, we examined it at single nucleotide polymorphism (SNP), gene, and pathway levels.

Results: Overall, 16 genome-wide significant loci (15 unique loci) (p _{meta-analysis} < 5 × 10⁻⁸) and 22 genes (21 unique genes) were identified between AD and frailty using cross-trait meta-analysis. The 8 shared loci implicated 11 genes: CLRN1-AS1, CRHR1, FERMT2, GRK4, LINC01929, LRFN2, MADD, RP11-368P15.1, RP11-166N6.2, RNA5SP459, and ZNF652 between AD and FI, and 8 shared loci between AD and FFS implicated 11 genes: AFF3, C1QTNF4, CLEC16A, FAM180B, FBXL19, GRK4, LINC01104, MAD1L1, RGS12, ZDHHC5, and ZNF521. The loci 4p16.3 (GRK4) was identified in both meta-analyses. The colocalization analysis supported the results of our meta-analysis in these loci. The gene-based analysis revealed 80 genes between AD and frailty, and 4 genes were initially identified in our meta-analyses: C1QTNF4, CRHR1, MAD1L1, and RGS12. The pathway analysis showed enrichment for lipoprotein particle plasma, amyloid fibril formation, protein kinase regulator, and tau protein binding.

Conclusion: Overall, our results provide new insights into the genetics of AD and frailty, suggesting the existence of non-causal shared genetic mechanisms between these conditions.

Keywords

frailty index, frailty phenotype, GWAS, colocalization, Mendelian randomization, genetic correlation, gene association, pathway analysis

DOI

10.3389/fgene.2024.1376050

PMID

38706793

PMCID

PMC11069310

PubMedCentral® Posted Date

4-19-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes