Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity

Beekman, Marian; Nederstigt, Christa; Suchiman, H. Eka D.; Kremer, Dennis; Breggen, Ruud van der; Lakenberg, Nico; Alemayehu, Wendimagegn; Craen, Anton J. M. de; Westendorp, Rudi G.J.; Boomsma, Dorret I.; Geus, Eco J. C. de; Houwing-Duistermaat, Jeanine J.; Heijmans, Bastiaan T.; Slagboom, P. Eline

doi:10.1073/pnas.1003540107

Cited by 143 publications

(133 citation statements)

References 32 publications

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“…To explain this finding, the authors assume that the risk alleles included in the analyses were mainly related to beta cell function, whereas the better glucose metabolism in the offspring was due to better insulin sensitivity. Alternatively, further results from the Leiden Longevity Study suggest that alleles protecting from disease rather than risk alleles may determine longevity [14]: long-lived individuals and younger controls did not differ in the number of risk alleles associated with cardiovascular disease, cancer and diabetes, and protective alleles may have a stronger effect on longevity than cumulated risk alleles.…”

Section: Discussionmentioning

confidence: 99%

Associations between longevity of parents and glucose regulation in their offspring: the KORA S4/F4 Study

et al. 2012

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Aims Type 2 diabetes was less prevalent in studies of the offspring of centenarians and a separate study of nonagenarian siblings. We examined whether this reduction would also be found when less extreme criteria of parental longevity (a lifespan of at least 80 years) were applied. Moreover, we looked for an association between parental longevity and incidence of dysglycaemia, which has not yet been reported for a population-based study group. Methods Baseline and 7-year follow-up data on 55-74-year-old participants in the population-based German Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort study were used for the analyses. Participants whose parents had died from traumatic causes were excluded. Diabetes was assessed by validated physician diagnosis or OGTTs. Using logistic regression models, adjusted OR and 95% CIs were calculated for the associations between parental longevity and the prevalence or incidence of dysglycaemia, which was defined as including either type 2 diabetes or prediabetes (defined in this study as comprising impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]). Results In age-and sex-adjusted models, the prevalence of type 2 diabetes was lower in individuals with one (OR 0.63, 95% CI 0.43, 0.93) or two (OR 0.46, 95% CI 0.25, 0.85) long-lived parents. Among participants with normal glucose tolerance at baseline, the odds of incident dysglycaemia were lower in those with one (OR 0.65, 95% CI 0.40, 1.03) or two long-lived parents (OR 0.46, 95% CI 0.22, 0.96) after adjustment for age and sex. Conclusions/interpretation This study showed that longevity of the parents, defined by a lifespan of at least 80 years, was associated with a lower prevalence and incidence of dysglycaemia in their offspring in an older German population.

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Section: Discussionmentioning

confidence: 99%

Associations between longevity of parents and glucose regulation in their offspring: the KORA S4/F4 Study

et al. 2012

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“…As extreme longevity appears to be a result of genetic factors more than environmental ones, when compared to an average lifespan, significant effort has gone into determining which genetic variants can slow aging and diminish the risk for age‐related diseases. Interestingly, the Leiden Longevity Study showed that, by GWAS, genomes of nonagenarians carry the same number of disease risk alleles for coronary artery disease, cancer and type 2 diabetes as young controls (Beekman et al ., 2010). These results hint toward the perception that these long‐lived individuals could carry “protective genes” that may work in general cellular defense mechanisms, for example, against oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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“…Even more disappointing result is that some genes predisposing to geriatric diseases discovered by GWAS appear to be not correlated with human longevity (Beekman et al 2010;Deelen et al 2011). This result questions whether findings obtained from GWAS may provide insights into the bio-genetic mechanisms underlying a healthy lifespan.…”

Section: Introductionmentioning

confidence: 99%

“…The other approach focuses on genetics of individuals with exceptionally long life Melzer et al 2007;De Benedictis et al 2001;Willcox et al 2008a). Despite notable progress of these approaches (Salvioli et al 2006;Christensen et al 2006;Teslovich et al 2010;Barzilai et al 2003;Koropatnick et al 2008;Willcox et al 2008a;Flachsbart et al 2009;Sebastiani et al 2010;Ku et al 2010;Bloss et al 2011), unraveling the role of genes in regulating health and lifespan and, consequently, potential of these factors for effective interventional strategies is still very limited (Manolio et al 2008;Cutler and Mattson 2006;McClellan and King 2010;Gibson 2009;Goldstein 2009;Plomin et al 2009;Gorlov et al 2008;Lunetta et al 2007;Newman et al 2010;Beekman et al 2010) explaining only a small fraction of genetic susceptibility (Frazer et al 2009;Kraja et al 2011). For instance, combined associations of 13 SNPs with blood pressure (BP) revealed by the CHARGE (Levy et al 2009) and Global BPgen (Newton-Cheh et al 2009) consortia explained less than 2% of the BP variance (Kraja et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Genomics of human health and aging

Kulminski

Culminskaya

2011

AGE

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Despite notable progress of the candidategene 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., RR02.9, p 05.0× 10 −66 ), onset of CVD (e.g., RR01.6, p04.6×10 −17 ), and onset of cancer (e.g., RR01.6, p01.5×10 −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 (p03.6×10 −10 ) enrichment of non-synonymous SNPs (N027) 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 cardiovascular (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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Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity

Cited by 143 publications

References 32 publications

Associations between longevity of parents and glucose regulation in their offspring: the KORA S4/F4 Study

Associations between longevity of parents and glucose regulation in their offspring: the KORA S4/F4 Study

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

Genomics of human health and aging

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