the online version, at doi:

/j.mad.

References Anselmi, C.V., Malovini, A., Roncarati, R., Novelli, V., Villa, F., Condorelli, G., Southern Italian Centenarian Study. Rejuvenation Res.

,

–

Barrett, J.C., Hansoul, S., Nicolae, D.L., Cho, J.H., Duerr, R.H., Rioux, J.D., Brant, Silverberg, M.S., Taylor, K.D., Barmada, M.M., Bitton, A., Dassopoulos, T., Lathrop, M., Belaiche, J., Dewit, O., Gut, I., Heath, S., Laukens, D., Mni, Rutgeerts, P., Van Gossum, A., Zelenika, D., Franchimont, D., Hugot, J.P., Vos, M., Vermeire, S., Louis, E., Cardon, L.R., Anderson, C.A., Drummond, Nimmo, E., Ahmad, T., Prescott, N.J., Onnie, C.M., Fisher, S.A., Marchini, J., J., Bumpstead, S., Gwilliam, R., Tremelling, M., Deloukas, P., Mansfield, J., D., Satsangi, J., Mathew, C.G., Parkes, M., Georges, M., Daly, M.J.,

wide association defines more than

distinct susceptibility loci for disease. Nat. Genet.

,

–

Blanche´, H., Cabanne, L., Sahbatou, M., Thomas, G.,

A study of centenarians: are ACE and APOE associated with longevity? CR Acad. Sci.

,

–

Browning, B.L., Browning, S.R.,

A unified approach to genotype and haplotype-phase inference for large data sets of trios and individuals. Am. J. Hum. Genet.

,

–

Chen, Y., Xiong, D.H., Guo, Y.F., Pan, F., Zhou, Q., Zhang, F., Deng, H.W., Pathway-based genome-wide association analysis identified the of Ephri

-Ep

pathway for femoral neck bone geometry. Bone

, of human longevity: challenges and insights. Nat. Rev. Genet.

,

–

Coon, K.D., Myers, A.J., Craig, D.W., Webster, J.A., Pearson, J.V., Lince, D.H., V.L., Beach, T.G., Leung, D., Bryden, L., Halperin, R.F., Marlowe, L., Kaleem, Walker, D.G., Ravid, R., Heward, C.B., Rogers, J., Papassotiropoulos, A., E.M., Hardy, J., Stephan, D.A.,

A high-density whole-genome study reveals that APOE is the major susceptibility gene for sporadic Alzheimer’s disease. J. Clin. Psychiatry

,

–

Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A.,

Gene dose of protein E type

allele and the risk of Alzheimer’s disease in late onset Science

,

–

D., van der Breggen, R., Suchiman, H.E., Lakenberg, N., van den Akker, Passtoors, W.M., Tiemeier, H., van Heemst, D., de Craen, A.J., Rivadeneira, F., Geus, E.J., Perola, M., van der Ouderaa, F.J., Gunn, D.A., Boomsma, D.I., linden, A.G., Christensen, K., van Duijn, C.M., Heijmans, B.T., termaat, J.J., Westendorp, R.G., Slagboom, P.E. Genome-wide association identifies a single major locus contributing to survival into old age; the locus revisited. Aging Cell, in press. Devlin, B., Roeder, K.,

Genomic control for association studies. Biometrics

–

Esparza-Gordillo, J., Weidinger, S., Folster-Holst, R., Bauerfeind, A., Ruschendorf, Schreiber, S., Franke, A., Vogler, R., Heath, S., Baurecht, H., Novak, N., E., Illig, T., Lee-Kirsch, M.A., Ciechanowicz, A., Kurek, M., Piskackova, T., M., Lee, Y.A., Ruether, A.,

A common variant on chromosome

q

associated with atopic dermatitis. Nat. Genet.

,

–

S., Schreiber, S., Nebel, A.,

Association of FOXO

A variation with

References

Anselmi, C.V., Malovini, A., Roncarati, R., Novelli, V., Villa, F., Condorelli, G., Bellazzi, R.,Puca,A.A.,2009.AssociationoftheFOXO3Alocuswithextremelongevityina

A previous meta-analysis of four prospective cohort studies revealed a statistically significant and replicated association of rs9664222 with longevity (defined as reaching 90 years and older) (Newman et al., 2010). This SNP did not show any association in our large case–control samples (P = 0.611). This CCA result could be due to the different designs and/or levels of statistical power of the two studies. Moreover, we also tested the 33 polymorphisms from Sebastiani et al. (in press) in our imputed GWAS data set, of which SNP rs2075650 that is in LD with the known APOE alleles (Sebastiani et al., in press) showed a significant association in our German sample. Also the Dutch GWAS identified an APOE-related SNP as the most relevant marker with a deleterious effect on survival into old age. No other major longevity locus was found (Deelen et al., in press). Thus, our and the independent Dutch study (Deelen et al., in press) both strengthen the conclusion that APOE is a very important genetic factor and it may very well be the most relevant one influencing human longevity.

In summary, the GWAS, as it was carried out in our study, revealed apart from APOE no novel candidate genes for longevity in humans. Larger samples, a more specific and genetically enriched longevity phenotype (so-called ‘super-centenarians’) or a meta- analysis involving several thousands of participants may be required to successfully and reliably identify additional genes through a GWAS. In addition, some genetic factors involved in longevity could not be detected in the present study on principal ground, including low-frequency polymorphisms, copy-number variations or epigenetic changes. Furthermore, it is noteworthy that although individual-specific mechanisms may be important for longevity, our study only considers probabilities on a population level. In the future, a genome-wide pathway-based approach (Chen et al., 2009; Luo et al., 2010) could be a useful means to explore the

Marciante, K.D., Massaro, J.M., Miljkovic, I., Nalls, M.A., Hernandez, D., Uh, H.W., Uitterlinden, A.G., Vaupel, J.W., Walston, J., Westendorp, R.G., T.B., Lumley, T., van Duijn, C.M., Murabito, J.M.,

A meta-analysis of genome-wide association studies of survival to age

years or older: Cohorts for Heart and Aging Research in Genomic Epidemiology J. Gerontol. A Biol. Sci. Med. Sci.

,

–

A., Solfrizzi, V.,

Vascular genetic factors and human longevity. Ageing Dev.

,

–

Pawlikowska,L.,Hu,D.,Huntsman,S.,Sung, A.,Chu,C., Chen,J.,Joyner, N.J., Hsueh, W.C., Reiner, A.P., Psaty, B.M., Atzmon, G., Barzilai, N., S.R., Browner, W.S., Kwok, P.Y., Ziv, E.,

Association of common variation in the insulin/IGF