Bioinformatic and genomic analysis identifies C allele of APOE rs7412 as the most prominent variant limiting extreme human longevity

Abstract

The genetic factors influencing human longevity have long been a subject of curiosity, linking ancient historical records with modern genomic research. This study seeks to identify key genetic contributors to lifespan by integrating genome-wide association studies (GWAS) with functional annotations across multiple biological databases. Among our findings, APOE emerged as one of the most prominent gene, with the rs7412-C variant showing a strong association with reduced lifespan due to its widely distributed across global populations. Additionally, we observed that rs449647-A and rs405509-T were more frequently found in regions with longer life expectancies, such as Asia, and were less common in African populations, suggesting a possible genetic influence on regional lifespan variations. These findings provide a basis for future research into the genetic mechanisms underlying aging and may contribute to the development of strategies to promote healthy aging.

Keywords: APOE; Bioinformatics; GWAS; Longevity; SNP.

Fig. 1

GWAS-Identified SNPs Associated with Longevity. This figure presents significant single-nucleotide polymorphisms (SNPs) associated with traits linked to human longevity, identified through a genome-wide association study (GWAS), 2849 SNPs were found to have robust statistical relevance across eight trait categories. Data were obtained from the GWAS catalog database (https://www.ebi.ac.uk/gwas/) on 2025 January 2nd, using keywords relevant to longevity research. This figure was created by BioRender.com.

Fig. 2

Workflow of the Longevity Study. The figure illustrates the study’s workflow, starting with the extraction of 2849 longevity-associated SNPs from the GWAS Catalog. Computational analysis using HaploReg expanded this to 34,261 SNP variants linked to 2262 genes. Functional annotation across 11 databases identified 55 genes with scores ≥ 5. Finally, biomarker analysis using the Mammalian Phenotype Level 4 database and validated against significant GWAS-mapped genes highlighted APOE as a key longevity-associated gene. This figure was created by BioRender.com.

Fig. 3

The analysis of KEGG pathways. The bar chart shows enriched pathways based on GWAS-derived genes, ranked by enrichment ratio. Significant pathways (dark blue, FDR ≤ 0.05) include the longevity regulating pathway and the PI3K-Akt signaling pathway both associated with lifespan regulation. Other pathways, such as those related to cancer and other diseases, highlight the genetic links between disease susceptibility and longevity. Data were obtained from www.kegg.jp/kegg/kegg1.html.

Fig. 4

Volcano plot analysis across various biological categories based on GWAS-derived genes. The analysis identifies significant enrichment in (A) biological processes (B) cellular components (C) Molecular function (D) human phenotype ontology (E) Human cell landscape emphasizes cell (F) DisGeNET gene-disease associations (G) miRNA enrichment and (H) kinase target enrichment. This comprehensive analysis highlights the various enrichment linked to longevity associated gene set. This figure were generated by https://www.webgestalt.org.

Fig. 5

Integration of longevity-associated genes with the MGI Mammalian Phenotype database. The network diagram illustrates the overlap between longevity-associated genes (green nodes) and the “premature death” phenotype (orange central node) in the MGI Mammalian Phenotype database. Genes meeting the scoring threshold of 5 were analyzed for their association with observable phenotypic outcomes in animal models. Red edges represent direct associations between genes and the “premature death” phenotype, while gray edges indicate additional phenotype relationships. This integrative analysis highlights the potential links between longevity-related genes and phenotypic traits, providing insights into lifespan regulation through experimental animal models. This figure was generated by https://maayanlab.cloud/enrichr-kg.

Fig. 6

Manhattan Plot of GWAS-derived significant genes associated with longevity and their overlap with premature death phenotypes from the MGI Mammalian Phenotype database. (Left) The genetic map from GWAS data, with significant genes represented by their −log10(p-value) along chromosomes. (Right) A Venn diagram highlighting the overlap between genes associated with the “premature death” phenotype (blue circle) and GWAS-derived top significance genes (orange circle). The central overlap identifies shared candidates, with APOE marked as a proposed biomarker for longevity. This figure was generated using RStudio.

Fig. 7

Forest plot of the association between rs429358-T allele and long lifespan. Forest plot showing the meta-analysis of studies investigating the association between the T allele and longevity. The random effects model estimates an odds ratio (OR) of 5.27 (95% CI 2.09–13.25), indicating that the T allele is 5.27 times more likely to be associated with longevity compared to the C allele. This forest plot was created using R studio.

Fig. 8

Forest plot of the association between rs7412-T allele and long lifespan. Forest plot showing the meta-analysis of studies investigating the association between the T allele and longevity. The random effects model estimates an odds ratio (OR) of 2.91 (95% CI 0.92–9.16), indicating that the T allele is associated with a 2.91 times more likely to be associated with longevity compared to the C allele. The common effect model yields an OR of 1.57 (95% CI 1.51–1.63). This forest plot was created using R studio.

Fig. 9

Allele Frequency Distribution of APOE Associate Missense SNP variant. The rs7412-C allele has become widespread across human populations and is associated with an increased risk of mortality, potentially influencing the natural limits of human longevity. Its global prevalence suggests a genetic factor that may have contributed to the decline of exceptionally long lifespans, as described in historical records, such as those of Adam, Noah, and Methuselah. This figure was created by BioRender.com.

Fig. 10

Allele Frequency Distribution of APOE Associate Intron SNP variant. The map illustrates the worldwide allele frequency distribution of the rs769449 SNP. The near-universal prevalence of the G allele suggests that its impact on longevity may be minimal, whereas the presence of the A allele could play a more critical role in influencing lifespan. This figure was created by BioRender.com.

Fig. 11

Allele Frequency Distribution of APOE Associate 2 KB Upstream SNP Variant. This map shows the allele frequencies of two regulatory SNPs, rs449647 and rs405509, in the APOE gene. The risk-associated alleles (rs449647-T, rs405509-G, in red) are most prevalent in Africa, aligning with lower life expectancy trends. In contrast, Asia has the lowest frequency of rs405509-G, consistent with high longevity in regions like Japan and South Korea. The longevity-associated allele rs449647-A (green) is most common in America, followed by Asia. These patterns suggest a genetic influence on lifespan differences across populations. This figure was created by BioRender.com.