Genetic evidence for common pathways in human age-related diseases

Abstract

Aging is the single largest risk factor for chronic disease. Studies in model organisms have identified conserved pathways that modulate aging rate and the onset and progression of multiple age-related diseases, suggesting that common pathways of aging may influence age-related diseases in humans as well. To determine whether there is genetic evidence supporting the notion of common pathways underlying age-related diseases, we analyzed the genes and pathways found to be associated with five major categories of age-related disease using a total of 410 genomewide association studies (GWAS). While only a small number of genes are shared among all five disease categories, those found in at least three of the five major age-related disease categories are highly enriched for apoliprotein metabolism genes. We found that a more substantial number of gene ontology (GO) terms are shared among the 5 age-related disease categories and shared GO terms include canonical aging pathways identified in model organisms, such as nutrient-sensing signaling, translation, proteostasis, stress responses, and genome maintenance. Taking advantage of the vast amount of genetic data from the GWAS, our findings provide the first direct evidence that conserved pathways of aging simultaneously influence multiple age-related diseases in humans as has been demonstrated in model organisms.

Keywords: Ink4a; ageing; aging; genetics; gerontogenes; human; inflammation; longevity gene.

Fig 1

Common pathways in aging and age-related disease. Aging is the single greatest risk factor for age-related disease, and it is well established that conserved genetic pathways of aging impact multiple age-related pathologies in model organisms, but the role of conserved pathways of aging in human age-related disease is unclear.

Fig 2

Genomewide association studies (GWAS) significant genes shared among age-associated diseases. Age-related disease categories show very little overlap of GWAS significant genes (A), with only 3 (0.15%) of genes identified shared among all groups, while the majority of genes appear to be detected in only one group. (B) Clustering of age-related disease categories by similarity shows that cardiovascular disease, metabolic disease, and other age-related pathologies are closely related, while cancers and neurodegenerative diseases represent the most distinct groups. (C) Number and category of genes shared among at least 3 age-related disease categories represent those predominately involved in immunity, inflammation, cell cycle regulation, and cholesterol metabolism. (D) GO analysis of these genes compared to the background set of all 1975 GWAS detected genes revealed that apolipoprotein metabolism is significantly and specifically enriched in this gene set.

Fig 3

A pathway-based analysis of age-related diseases. (A) Age-related disease groups were analyzed using a pathway-based approach by examining the GO terms associated with genomewide association studies identified genes rather than the genes themselves. (B) A comparison between age-related disease categories shows a more significant similarity between ontology terms than was observed using individual genes (7.6% vs. 0.15%). (C) Although the relative percentage of overlapping terms is greater the relative similarities between disease categories are unchanged as determined by unsupervised clustering.

Fig 4

Pathway analysis identified shared pathways among age-related diseases. Visualization of the GO terms shared by all five age-related disease categories reveals common pathways in human age-related disease. These include many canonical aging pathways identified in model organisms, such as nutrient-sensing signaling, proteostasis, and stress responses, as well as cholesterol metabolism, as was identified in the gene-based analysis. GO terms shared among age-related diseases are significantly enriched for similar terms compared to the background (P-value < 10⁻¹⁵, one-sided Wilcoxon rank-sum test, see Methods).