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Genomics of human health and aging

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Abstract

Despite notable progress of the candidate-gene and genome-wide association studies (GWAS), understanding the role of genes contributing to human health and lifespan is still very limited. We use the Framingham Heart Study to elucidate if recognizing the role of evolution and systemic processes in an aging organism could advance such studies. We combine throughput methods of GWAS with more detail methods typical for candidate-gene analyses and show that both lifespan and ages at onset of CVD and cancer can be controlled by the same allelic variants. The risk allele carriers are at highly significant risk of premature death (e.g., RR = 2.9, p = 5.0 × 10−66), onset of CVD (e.g., RR = 1.6, p = 4.6 × 10−17), and onset of cancer (e.g., RR = 1.6, p = 1.5 × 10−6). The mechanism mediating the revealed genetic associations is likely associated with biological aging. These aging-related phenotypes are associated with a complex network which includes, in this study, 62 correlated SNPs even so these SNPs can be on non-homologous chromosomes. A striking result is three-fold, highly significant (p = 3.6 × 10−10) enrichment of non-synonymous SNPs (N = 27) in this network compared to the entire qualified set of the studied SNPs. Functional significance of this network is strengthened by involvement of genes for these SNPs in fundamental biological processes related to aging (e.g., response to stimuli, protein degradation, apoptosis) and by connections of these genes with neurological (20 genes) and cardio-vascular (nine genes) processes and tumorigenesis (10 genes). These results document challenging role of gene networks in regulating human health and aging and call for broadening focus on genomics of such phenotypes.

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Acknowledgments

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. The Framingham Heart Study and the Framingham SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University. The Framingham SHARe data used for the analyses described in this manuscript were obtained through dbGaP (accession numbers phs000007.v7.p4 and phs000007.v14.p5). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or the NHLBI. We thank our colleagues, A. Yashin, S. Ukraitseva, and K. Arbeev, for fruitful discussion of the results. A.M.K. contributed to the study conception, design, statistical and biological analyses, interpretation of the results, and writing the manuscript. I.C. contributed to the study design, biological analyses, interpretation of the results, and writing the manuscript.

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  1. Center for Population Health and Aging, Duke University, Box 90408, Trent Hall, Room 002, Durham, NC, 27708, USA

    Alexander M. Kulminski & Irina Culminskaya

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  1. Alexander M. Kulminski
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  2. Irina Culminskaya
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Correspondence to Alexander M. Kulminski.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1

Statistics for 63 SNPs pre-selected at the first stage of the analyses according to tentative association with at least one of the four endophenotypes at genome-wide level p <10−6 (PDF 25 kb)

Online Resource 2

Conditional and unconditional minus-log-transformed p values for the 63 pre-selected SNPs. Blue color denotes original unconditional estimates. Red color shows the estimates conditional on three proxy SNPs, i.e., rs9330200, rs2292664, and rs5491. CVD denotes cardiovascular diseases, SBP denotes systolic blood pressure, and TC denotes total cholesterol (PDF 95 kb)

Online Resource 3

Associations of each of the three proxy SNPs with each of the four endophenotypes (PDF 11 kb)

Online Resource 4

Empirical Kaplan–Meier age patterns of probability of staying free of CVD or cancer. Curves show the age at onset of a–c CVD and d–f cancer through 2007 for the minor-allele carriers and major-allele homozygotes of a, d rs9330200, b, e rs2292664, and c, f rs5491. Crosses show censored individuals. HLE denotes “healthy life expectancy” defined as life without (a–c) CVD or (d–f) cancer. Letter “n” denotes the number of total/diseased individuals. CI confidence interval (PDF 184 kb)

Online Resource 5

Annotation of genes identified for 62 SNPs showing linkage disequilibrium and associations with phenotypes (PDF 61 kb)

Online Resource 6

Analysis of 50 genes for the revealed SNPs on enrichment in Gene Ontology (GO) biological processes (PDF 14 kb)

Online Resource 7

Analysis of 57 genes for the revealed SNPs on enrichment in Gene Ontology (GO) molecular function (PDF 15 kb)

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Kulminski, A.M., Culminskaya, I. Genomics of human health and aging. AGE 35, 455–469 (2013). https://doi.org/10.1007/s11357-011-9362-x

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  • DOI: https://doi.org/10.1007/s11357-011-9362-x

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