A total of 27 SNPs located in 25 genes showed evidence for association with lifespan in both gender groups (data not shown). Although the allelic effects of the matrix Gla protein (MGP) and the tumor necrosis factor (ligand) superfamily, member 11 (TNFSF11) were insignificant, these genes showed notable genotypic effects in the overdominant model. As shown in Table 1, TG heterozygotes of the rs1054016 were observed at lower frequencies among the old age group compared to the young age group (OR 0.45 and 0.32 and 0.30; P = 4 × 10-4 and 0.001 for each group of nonagenarians adjusted for gender and males ≥ 90, respectively). All 27 genes consis- tently showed evidence for association with lifespan in both allele- and genotype-based analyses. In particular, six genes showing significant associa- tion with a P value less than 0.01 (ADCY2, ade- nylate cyclase 2 (brain), PPP1R1A; LYN, V-yes-1 Yamaguchi sarcoma viral related oncogene homolog; PAX4, ALDH2, IL12RB2) attracted considerable attention as candidate genes affecting lifespan in Koreans. The results revealed significant gender differences in genetic associations with

Haplotypic association

Among the 69 genes that showed significant ge- notypic association, we found significant association with longevity in 12 genes by using tagSNPs for 32 genes with at least 3 genotyped SNPs. Among nine genes that consistently yielded significant evidence of allelic, genotypic, and haplotypic asso- ciations with longevity (i.e. HK2, hexokinase 2; ERBB4, v-erb-a erythroblastic leukemia viral onco- gene homolog 4 (avian); PCSK1, proprotein con- vertase subtilisin/kexin type 1; ITK, IL2-inducible T-cell kinase; EGFR; PAX4; LPL, lipoprotein lipase; LYN; and CDK10, cyclin-dependent kinase 10), only the PCSK1 (P = 0.008), EGFR (P = 0.003), PAX4 (P = 0.008), and LYN (P = 0.002) remained significant after the Bonferroni correction for multiple testing of haplotypes in each gene (Table 2). Figure 1 summarizes the -log (P value) obtained 10 from three different analyses of association for these four genes.

The presence of the G allele of rs155979 in the CGA haplotype of PCSK1 decreased lifespan among the group of nonagenarian adjusted by sex (OR 0.54). The G allele of rs712700 increased

Nonagenarian men

A total of 43 SNPs located in 31 genes including four missense mutations located in each of euka-

Table 1. Results from the allele-and genotype-based analyses for individual SNPs showing evidence for association with longevity (P 0.01).

Gene Allelec Number Na SNP Functionb OR (95%CI) P value Location Modeld Case Control A. All ≥ 90 adjusted by sex ADCY2 2 rs326146 Ile881Val G/A 171/101 305/123 1.46 (1.05-2.03) 0.024 5p15.3 Additve 58/55/23 108/86/18 1.43 (1.03-1.97) 0.030 rs326175 3' UTR C/G 161/113 293/137 1.53 (1.11-2.11) 0.009 Additve 50/61/26 96/98/19 1.53 (1.11-2.12) 0.009 PCSK1 3 rs155979 2 kb∼5' C/G 225/49 315/115 0.61 (0.42-0.90) 0.012 5q15-q21 Dominant 95/35/7 113/85/15 0.53 (0.33-0.83) 0.005 PIK3C2G 2 rs4237973 2 kb∼5' T/C 190/82 328/100 1.51 (1.06-2.14) 0.022 12p12 Dominant 60/70/6 122/82/8 1.81 (1.16-2.82) 0.009 MGP 1 rs1800802 2 kb∼5' T/C 197/77 281/149 0.77 (0.55-1.08) 0.132 12p13.1-p12.3 Overdominant 75/47/15 45/54/7 0.44 (0.25-0.77) 0.003 PPP1R1A 2 rs1691595 2 kb∼5' T/C 244/30 405/21 2.44 (1.35-4.42) 0.003 12q13.2 Additve 110/24/3 191/21/0 2.35 (1.31-4.20) 0.004 TNFSF11 1 rs1054016 3' UTR G/T 110/162 183/239 1.09 (0.80-1.50) 0.579 13q14 Overdominant 57/48/31 62/114/33 0.45 (0.28-0.70) 4×10-4 B. Male ≥ 90 PCSK1 3 rs155979 2 kb∼5' C/G 92/20 186/76 0.53 (0.31-0.92) 0.025 5q15-q21 Dominant 39/14/3 63/56/10 0.42 (0.21-0.81) 0.008 PAX4 3 rs327519 3' UTR A/G 101/9 256/4 5.70 (1.72-18.94) 0.004 7q32 Additve 47/7/1 124/4/0 5.00 (1.50-16.68) 0.005 rs712700 3' UTR A/G 62/44 184/70 1.87 (1.16-3.00) 0.010 Additve 19/24/10 66/49/10 1.82 (1.13-2.93) 0.013 rs327517 Synonymous A/G 103/9 254/4 5.55 (1.67-18.42) 0.005 Additve 48/7/1 123/4/0 4.86 (1.46-16.20) 0.005 LYN 10 rs1980042 Intron T/C 80/32 220/42 2.10 (1.24-3.55) 0.006 8q13 Dominant 29/22/5 94/30/5 2.50 (1.30-4.80) 0.006 rs1979128 Intron A/G 80/32 220/42 2.10 (1.24-3.55) 0.006 Dominant 29/22/5 94/30/5 2.50 (1.30-4.80) 0.006 JAK2 1 rs2274471 Intron T/C 83/29 213/47 1.58 (0.93-2.68) 0.088 9p24 Recessive 34/15/7 84/41/3 5.95 (1.48-23.95) 0.008 ABCC8 2 rs757110 Ser1369Ala T/G 63/45 150/112 0.96 (0.61-1.51) 0.848 11p15.1 Overdominant 13/37/4 47/53/29 3.12 (1.59-6.12) 6×10-4 PPP1R1A 2 rs1691595 2 kb∼5' T/C 97/15 248/12 3.20 (1.44-7.07) 0.004 12q13.2 Additve 44/9/3 117/12/0 2.77 (1.28-5.96) 0.008 ALDH2 1 rs671 Lys504Glu G/A 83/27 227/35 2.11 (1.20-3.70) 0.009 12q24.2 Dominant 30/23/2 98/29/2 2.63 (1.35-5.13) 0.004 TNFSF11 1 rs1054016 3' UTR G/T 48/62 111/143 1.00 (0.64-1.57) 0.991 13q14 Overdominant 23/16/16 36/70/19 0.32 (0.16-0.64) 0.001 CDK10 3 rs2075880 Intron G/A 38/70 120/142 1.56 (0.98-2.48) 0.061 16q24 Dominant 25/20/9 34/70/25 0.42 (0.21-0.81) 0.009 C. Female ≥ 90 IL12RB2 1 rs2030071 Intron C/T 159/3 156/16 0.18 (0.05-0.64) 0.008

aNumber of informative markers for the gene; bUTR, un-translated region; cAncestral alleles were shown in bold; dBest fitting mode of inheritance: Only SNPs showing a significant genotypic OR from the most significant regression model (P ＜ 0.01) for the gene were shown.

Table 2. Results from the haplotype-based analyses for candidate genes showing evidence for association with longevity (P 0.05/Number of haplotypes).