Dissecting the shared genetic architecture between Alzheimer's disease and frailty: a cross-trait meta-analyses of genome-wide association studies

Nitesh Enduru; Brisa S Fernandes; Zhongming Zhao

doi:10.3389/fgene.2024.1376050

Dissecting the shared genetic architecture between Alzheimer's disease and frailty: a cross-trait meta-analyses of genome-wide association studies

Front Genet. 2024 Apr 19:15:1376050. doi: 10.3389/fgene.2024.1376050. eCollection 2024.

Authors

Nitesh Enduru^{1

2}, Brisa S Fernandes¹, Zhongming Zhao^{1

2

3}

Affiliations

¹ Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United States.
² Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States.
³ Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.

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: GWAS; Mendelian randomization; colocalization; frailty index; frailty phenotype; gene association; genetic correlation; pathway analysis.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was partially supported by National Institutes of Health grants awarded to ZZ (U01AG079847, R01LM012806, R01LM012806-07S1, and R03AG077191). We thanked the technical support from the Cancer Prevention and Research Institute of Texas (CPRIT RP180734). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.