An interesting aspect of the gene-set analysis is whether the nominal significance of BER, HRR and RECQ was mainly driven by one gene or by the combined effect of several genes. For RECQ and HRR, the associations were driven primarily by WRN and RAD52, respectively. The latter might indicate that variation in one of the sub- units of the rad51/rad52/rad54 protein complex may be sufficient to modify the function of the entire HRR. Our results could also indicate that RAD52 and WRN have roles beyond HRR and RECQ. WRN is a clear example of this, as it takes part in three of nine sub-processes. Similarly, one study indicates that rad52 may affect BER via an interaction with ogg1.48 Finally, as our definition of the sub-processes is based on existing knowledge of DNA-damage response and repair mechanisms, we cannot exclude that additional cross-talks between the sub-processes are yet to be discovered. Contrary to this, the association of BER appears scattered over the entire gene-set, suggesting that variation in different parts of the sub-process may have consequences for longevity. Considering the central role of oxidative damage to several proposed biological theories of aging,22,49 the fact that we observe this for BER, the DNA repair process primarily responsible for repair of oxidative DNA lesions, is indeed interesting.

to this, the association of BER appears scattered over the entire suggesting that variation in different parts of the sub-process have consequences for longevity. Considering the central role of damage to several proposed biological theories of aging,22,49 fact that we observe this for BER, the DNA repair process primarily for repair of oxidative DNA lesions, is indeed interesting.

is obviously how the details and widths of the sub-processes are identified. This is in general a complicated task as there is no gold standard and available databases may lack sufficient detail36 and accordance in the pathway composition.50 Consequently, it is possible that some relevant genetic variation is not covered in the present study.

CONCLUSION

In this study, we investigated the association between human long- evity and genetic variation in nine sub-processes of DNA-damage response and repair, all considered to have key roles in maintenance of genetic stability and the aging process. We observed significant support for an association of the entire pathway with longevity. In the competitive analysis, we furthermore found BER, HRR and RECQ to be nominally significantly more associated with longevity than other sub-processes, although this did, in general, not remain significant

An intriguing aspect of human longevity is the difference in survival, a difference which has been suggested, at in part, to have a genetic basis.51 A sex-stratified self-contained based analysis of all SNPs investigated showed significance for

for BER, the association was caused by several genes, which indicates that, of the entire pathway, variation in BER might influence longevity the most. Still, as these findings did not show replication in the German study population, more analyses are needed in additional study populations before final conclusion can be drawn.

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