For abbreviations see legend to Table 1.

 3.5 4ida-LOgio Reany0.5 0 108950 109000 109050 109100 109150cx Chromosomal position inACE1 FOXO3A   1822747761518716311369114070237512200646)3519007                              LD structure from HapMap data      (01  Association results in German centenariansGenotyped in Germans © Genotyped in GermansGenotyped in Germans © Genotyped in Germans and Dutchin perfect LD with significant SNPs typed in Japanese© — Inperfect LD with significant SNPs typed in JapaGenotyped in Germans and in DutchGenotyped in Germans and in Dutch © No HapMap data availablein perfect LD with significant SNPs typed in Japanese Corresponds to p value 0.05Genotyped only in JapanesePerfect LD between SNPs typedin Japanese and Germans

Fig. 1. Fine mapping of the FOXO3A region on chromosome 6 (German centenarian sample). The physical position (in kb) of all 16 genotyped SNPs with their allele-based P values ((cid:3)log P German centenarian sample) and a schematic representation of the gene structure NM(cid:1)201559 are shown. 10 CCA, Coordinates refer to National Center for Biotechnology Information genome assembly build 36. Plotted association results (PAR) of SNPs that have previously been typed in the Dutch sample are indicated by a pentagon; PAR of SNPs that are in perfect LD with SNPs typed in the Japanese sample (according to CEU HapMap data) are indicated by a gray curb; PAR with no available HapMap data are presented as a black circle. The LD plot of the locus is based on the measure r2 and was generated with Haploview by using CEU HapMap data. The markers typed in the German sample are indicated by a gray box; markers typed in Germans that are in perfect LD with the significant SNPs typed in the Japanese (according to CEU HapMap data) are indicated by a white circle; markers typed in the German and Dutch samples are indicated by a double gray box; markers typed in the German and Dutch samples that are in perfect LD with the significant SNPs typed in the Japanese (according to CEU HapMap data) are indicated by a white circle and a double gray box; markers only genotyped in the Japanese sample with no corresponding P values in the German sample are indicated by a black CCA circle; perfect LD between the SNPs typed in the Japanese and the German samples (according to CEU HapMap data) is indicated by a white circle in the

selpmashctuDdnahcnerF,namreG,esenapaJmorfscitsitatsnoitaicossaA3OXOFfonosirapmoC.3elbaT detaicossayltnacfiingiSnisPNSdetaicossayltnacfiingiSsPNSdetaicossayltnacfiingiS nisPNS *hctuDnisPNS*hcnerF*snamreGnisPNSdetaicossayltnacfiingiSesenapaJni DLgnorts FAniMFAniMhtiwniM trohocFAniMFAniMFAniM99–59FAniMFAniMFAniM’xoclliWFAFAniM P78’slortnocPsnairanetnecslortnoc§Psraey‡PILL†Psnairanetnecslortnoc2rsPNSPylredleslortnocPNS 112.0204.0030.0514.0600.0834.0873.017041196sr1000.0 (cid:5)173.0552.02922082sr 790.0924.0393.0033.0004.0150.0514.0700.0044.0283.01320867sr sn563.0453.0483.0204.0850.0714.0600.0544.0583.018822082sr 854.0104.0180.0714.0010.0444.0783.010922082sr 983.0113.0520.0133.07000.0663.0592.088.09320049sr2000.0743.0842.04624672sr 983.0113.0520.0133.07000.0663.0592.019320049sr6000.0043.0842.059771231sr sn392.0182.088.00693512sr ACC .hctuDdnahcnerF,snamreGnidepytsPNSdnanemesenapaJnidepytsrekramehtneewtebatadpaMpaHUECmorfseulavDL,2r .nemesenapaJnidepytsPNStnacfiingishtiwDLgnortsrotcefrepnieratahthctuDro,hcnerF,snamreGnidepytsPNSrofscitsitatsnoitaicossA*

For abbreviations see legend to Table 1.

et al. were in perfect or very high LD with 5 highly markers in our study (Fig. 1 and Table 3). In addition, FOXO3A LD structure is comparable in Europeans and (HapMap data for CEU and JPT) (see Fig. S1). the allele frequencies differed between Germans and it is noteworthy that in both populations the frequency followed the same trend, with a significant increase the minor allele in the LLI relative to the younger controls 3). In the Japanese sample, only SNP rs2802292 was for further analyses. The OR of this SNP was larger the homozygote of the minor allele than for the heterozygote the homozygote of the major allele was taken as the genotype), suggesting an additive effect (12) (Table 5). the German centenarian sample (subset B), rs2802288, is in perfect LD with Willcox et al.’s rs2802292 (according CEU HapMap data), revealed no evidence for an additive (Table 5). Comparisons of the homozygote, the hetero- and carriers of the minor allele with the homozygote of “no   major allele all yielded similar ORs of 1.5 (P 0.025, and 0.0016, respectively), whereas there was no differ- between the heterozygote and the homozygote of the minor ywei'’  (OR 1.01, P 0.97) (Table 5). These findings suggest dominant effect for the minor allele of rs2802288 in the population. However, because the corresponding con- intervals (C.I.) reported by us (Table 5) and Willcox et are rather large, the available data do not allow us to ascertain there is an additive or a dominant effect.

The influence of FOXO3A variation on longevity had also been examined in the Dutch Leiden 85-plus study using both single-point and haplotype analysis (15). None of the 11 tested SNPs yielded a significant result when 2 elderly cohorts (aged 85 and 88–92 years) were, in a cross-sectional manner, compared with a younger control sample (aged 27–36 years). Four of these SNPs were part of our marker panel (rs2802288, rs2883881, rs12200646, and rs13220810), and in contrast to the Leiden results, 3 of them were significantly associated in German centenarians (Table 2). Furthermore, one of the SNPs tested in the Dutch sample (rs2153960) was in strong LD with the SNP rs13217795 that was highly associated in the Japanese men from Hawaii (P At AL> — 0.0006; r2  0.88 between rs13217795 and rs2153960 according to CEU HapMap data; Table 3).