TY - JOUR
T1 - Human longevity and variation in DNA damage response and repair: Study of the contribution of sub-processes using competitive gene-set analysis
AU - Debrabant, Birgit
AU - Sørensen, Mette
AU - Flachsbart, Friederike
AU - Dato, Serena
AU - Mengel-From, Jonas
AU - Stevnsner, Tinna
AU - Bohr, Vilhelm A
AU - Kruse, Torben A
AU - Schreiber, Stefan
AU - Nebel, Almut
AU - Christensen, Kaare
AU - Tan, Qihua
AU - Christiansen, Lene
N1 - Shared first authorship
PY - 2014/9
Y1 - 2014/9
N2 - Shared first authorshipDNA-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.
AB - Shared first authorshipDNA-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.
KW - DNA-damage response and DNA repair
KW - SNPs
KW - case-control data
KW - competitive gene-set analysis
KW - human longevity
KW - Humans
KW - Middle Aged
KW - Male
KW - DNA Repair/genetics
KW - Case-Control Studies
KW - Longevity/genetics
KW - Aged, 80 and over
KW - Female
KW - Aged
KW - DNA Repair Enzymes/genetics
KW - Polymorphism, Single Nucleotide
KW - DNA Damage
U2 - 10.1038/ejhg.2013.299
DO - 10.1038/ejhg.2013.299
M3 - Journal article
C2 - 24518833
SN - 1018-4813
VL - 22
SP - 1131
EP - 1136
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 9
ER -