Review: a meta‐analysis of GWAS and age‐associated diseases
Open accessAbstract
Summary: Genome‐Wide Association studies (GWAS) offer an unbiased means to understand the genetic basis of traits by identifying single nucleotide polymorphisms (SNPs) linked to causal variants of complex phenotypes. GWAS have identified a host of susceptibility SNPs associated with many important human diseases, including diseases associated with aging. In an effort to understand the genetics of broad resistance to age‐associated diseases (i.e., ‘wellness’), we performed a meta‐analysis of human GWAS. Toward that end, we compiled 372 GWAS that identified 1775 susceptibility SNPs to 105 unique diseases and used these SNPs to create a genomic landscape of disease susceptibility. This map was constructed by partitioning the genome into 200 kb ‘bins’ and mapping the 1775 susceptibility SNPs to bins based on their genomic location. Investigation of these data revealed significant heterogeneity of disease association within the genome, with 92% of bins devoid of disease‐associated SNPs. In contrast, 10 bins (0.06%) were significantly (P < 0.05) enriched for susceptibility to multiple diseases, 5 of which formed two highly significant peaks of disease association (P < 0.0001). These peaks mapped to the Major Histocompatibility (MHC) locus on 6p21 and the INK4/ARF (CDKN2a/b) tumor suppressor locus on 9p21.3. Provocatively, all 10 significantly enriched bins contained genes linked to either inflammation or cellular senescence pathways, and SNPs near regulators of senescence were particularly associated with disease of aging (e.g., cancer, atherosclerosis, type 2 diabetes, glaucoma). This analysis suggests that germline genetic heterogeneity in the regulation of immunity and cellular senescence influences the human healthspan.
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GWAS have shown that the INK4/ARF locus, encoding p15INK4B, p16 and ARF, is a hotspot for susceptibility to ageing-associated diseases including cancer, diabetes and cardiovascular disease, and to physical dysfunction with advancing age.
“Genome-wide association studies have recently revealed that the INK4/ARF gene locus, encoding p15INK4B, p16 and ARF, key effectors of the senescence growth arrest, is a genomic hotspot for susceptibility to several ageing-associated diseases, including cancer, diabetes and cardiovascular disease167,168, and physical dysfunction in people with advancing age169,170.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [167]
SNPs located near regulators of senescence and inflammation are particularly associated with diseases of ageing such as cancer, CVD, and type 2 diabetes, with the strongest association at a variant in CDKN2A encoding p16INK4A.
“Interestingly, SNPs located near regulators of senescence and inflammation are particularly associated with diseases of ageing, such as cancer, CVD, and type 2 diabetes, and the strongest association was found with a variant in the CDKN2A gene, which encodes the p16INK4A protein that is over-expressed in many forms of senescence.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [91]
The CDKN2A findings were replicated in a meta-analysis including 410 genome-wide association studies.
“These findings were replicated in a meta-analysis that included 410 genome-wide association studies91,92.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [91]
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- Authors
- Jeck, W. R., Siebold, A. P., & Sharpless, N. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Sharpless, Norman E.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2012-08-30
- Volume
- 11
- Issue
- 5
- Pages
- 727-731
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3444649
- OpenAlex
- W2165766480
- Cited by
- 204
- References
- 24
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 10 · 2023: 6 · 2022: 17 · 2021: 17 · 2020: 14 · 2019: 14 · 2018: 16 · 2017: 19 · 2016: 14 · 2015: 27 · 2014: 14 · 2013: 18 · 2012: 2
- FWCI
- 11.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ag024379-15)
- National Institute on Aging (R01-AG024379, F30AG041567)
- National Institute of Environmental Health Sciences (P30ES010126)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- age-related diseases, MHC locus, cellular senescence, inflammation, healthspan, cancer, atherosclerosis, type 2 diabetes, glaucoma
- MeSH terms
- Aged, Aged, 80 and over, Aging, Chronic Disease, Humans, Genome-Wide Association Study
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