Abstract
DNA-damage response and repair are crucial to maintain genetic stability, and are consequently considered central to aging and longevity. Here, we investigate whether this pathway overall associates to longevity, and whether specific sub-processes are more strongly associated with longevity than others. Data were applied on 592 SNPs from 77 genes involved in nine sub-processes: DNA-damage response, base excision repair (BER), nucleotide excision repair, mismatch repair, non-homologous end-joining, homologous recombinational repair (HRR), RecQ helicase activities (RECQ), telomere functioning and mitochondrial DNA processes. The study population was 1089 long-lived and 736 middle-aged Danes. A self-contained set-based test of all SNPs displayed association with longevity (P-value=9.9 × 10−5), supporting that the overall pathway could affect longevity. Investigation of the nine sub-processes using the competitive gene-set analysis by Wang et al indicated that BER, HRR and RECQ associated stronger with longevity than the respective remaining genes of the pathway (P-values=0.004–0.048). For HRR and RECQ, only one gene contributed to the significance, whereas for BER several genes contributed. These associations did, however, generally not pass correction for multiple testing. Still, these findings indicate that, of the entire pathway, variation in BER might influence longevity the most. These modest sized P-values were not replicated in a German sample. This might, though, be due to differences in genotyping procedures and investigated SNPs, potentially inducing differences in the coverage of gene regions. Specifically, five genes were not covered at all in the German data. Therefore, investigations in additional study populations are needed before final conclusion can be drawn.
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Acknowledgements
This study was supported by the Max-Planck Institute for Demographic Research, (Rostock, Germany), the INTERREG 4 A programme Syddanmark–Schleswig-K.E.R.N (by EU funds from the European Regional Development Fund), the European Union’s Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 259679, the National Institute on Aging (P01 AG08761), the RESOLVE project (FP7-HEALTH-F4-2008-202047) and the Novo Nordisk, the Aase and Ejnar Danielsen, the Brødrene Hartmann, the King Christian the 10th and the Einer Willumsens Mindelegat Foundations. The Danish Aging Research Center is supported by a grant from the VELUX Foundation, while Mette Soerensen is supported by an individual postdoctoral grant from The Danish Council for Independent Research – Medical Sciences.
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Debrabant, B., Soerensen, M., Flachsbart, F. et al. Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis. Eur J Hum Genet 22, 1131–1136 (2014). https://doi.org/10.1038/ejhg.2013.299
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DOI: https://doi.org/10.1038/ejhg.2013.299
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