Global test

To adjust for multiple testing, the significance level was set at the Bonferroni-corrected nominal P value (which is 0.05/(number of pathway or gene SNP sets tested)).

In this study, we used a modified version of the Global test (http://www.bioconductor.org/help/bioc-

Table 1 Characteristics of the insulin/IGF-1 signaling pathway proteins Protein Gene Entrez gene ID Chr Start (bp) End (bp) Size (kb) SNPs Coverage AKT1 AKT1 207 14 104,306,732 104,333,125 26.39 2 25.00% AKT2 AKT2 208 19 45,428,064 45,483,105 55.04 6 45.45% AKT3 AKT3 10000 1 241,718,158 242,073,509 355.35 25 50.00% BIM BCL2L11 10018 2 111,594,962 111,642,493 47.53 12 47.06% BCL-6 BCL6 604 3 188,921,859 188,946,169 24.31 6 23.81% CAT CAT 847 11 34,417,048 34,450,182 33.13 18 80.00% Cyclin D1 CCND1 595 11 69,165,054 69,178,423 13.37 3 27.27% Cyclin D2 CCND2 894 12 4,253,163 4,284,782 31.62 20 45.00% Cyclin G2 CCNG2 901 4 78,297,381 78,310,237 12.86 4 33.33% p27kip CDKN1B 1027 12 12,761,569 12,766,572 5.00 9 75.00% CBP CREBBP 1387 16 3,715,057 3,870,122 155.07 15 50.00% Deptor (mTORC2) DEPDC6 64798 8 120,955,081 121,132,338 177.26 47 61.90% p300 EP300 2033 22 39,818,560 39,906,027 87.47 6 50.00% Fas ligand FASLG 356 1 170,894,808 170,902,635 7.83 7 45.45% FOXO1 FOXO1 2308 13 40,027,801 40,138,734 110.93 19 65.38% FOXO3A FOXO3 2309 6 108,987,719 109,112,664 124.95 21 68.75% FOXO4 FOXO4 4303 X 70,232,751 70,240,109 7.36 3 NA G6P G6PC 2538 17 38,306,341 38,318,912 12.57 5 83.33% IGF1 IGF1 3479 12 101,313,775 101,398,508 84.73 20 47.06% IGF1R IGF1R 3480 15 97,010,284 97,325,282 315.00 102 56.34% IGF2 IGF2 3481 11 2,106,923 2,127,409 20.49 7 63.64% Insulin INS 3630 11 2,137,585 2,139,015 1.43 4 80.00% IR INSR 3643 19 7,063,266 7,245,011 181.75 52 50.00% IRR INSRR 3645 1 155,077,289 155,095,290 18.00 6 37.50% IRS1 IRS1 3667 2 227,304,277 227,371,750 67.47 11 53.33% IRS2 IRS2 8660 13 109,204,185 109,236,915 32.73 15 59.09% IRS4 IRS4 8471 X 107,862,383 107,866,263 3.88 2 NA PCAF KAT2B 8850 3 20,056,528 20,170,900 114.37 44 62.96% ERK2 MAPK1 5594 22 20,443,947 20,551,970 108.02 12 58.33% ERK1 MAPK3 5595 16 30,032,927 30,042,131 9.20 2 33.33% JNK1 MAPK8 5599 10 49,279,693 49,313,189 33.50 6 35.71% JNK2 MAPK9 5601 5 179,593,203 179,651,677 58.47 17 40.00% JNK3 MAPK10 5602 4 87,155,300 87,593,307 438.01 71 55.81% mSIN1 (mTORC2) MAPKAP1 79109 9 127,239,494 127,509,334 269.84 26 64.00% mLST8 (mTORC2) MLST8 64223 16 2,195,451 2,199,419 3.97 4 80.00% mTOR (mTORC2) MTOR 2475 1 11,089,176 11,245,195 156.02 11 50.00% PEPCK PCK1 5105 20 55,569,543 55,574,919 5.38 10 33.33% PDK1 PDPK1 5170 16 2,527,971 2,593,190 65.22 0 0.00% PHLPP1 PHLPP1 23239 18 58,533,714 58,798,646 264.93 41 64.29% PHLPP2 PHLPP2 23035 16 70,236,353 70,306,205 69.85 4 15.38% PI3K PIK3CA 5290 3 180,349,005 180,435,191 86.19 10 44.44% PIK3CB 5291 3 139,856,921 139,960,875 103.95 8 42.86% PIK3CD 5293 1 9,634,377 9,711,759 77.38 8 42.11% PIK3R1 5295 5 67,558,218 67,633,405 75.19 31 65.12%

1 Characteristics of the insulin/IGF-1 signaling pathway proteins

Protein Gene Entrez gene ID Chr Start (bp) End (bp) Size (kb) SNPs Coverage PIK3R2 5296 19 18,125,016 18,142,343 17.33 5 66.67% PIK3R3 8503 1 46,278,399 46,371,295 92.90 10 60.00% PP2A PPP2R5B 5526 11 64,448,756 64,458,523 9.77 3 37.50% Protor-1 (mTORC2) PRR5 55615 22 43,443,091 43,512,225 69.13 32 50.00% PTEN PTEN 5728 10 89,613,175 89,718,512 105.34 8 47.06% PTP1B PTPN1 5770 20 48,560,298 48,634,493 74.20 17 44.44% p130Rb2 RBL2 5934 16 52,025,852 52,083,061 57.21 3 33.33% RICTOR (mTORC2) RICTOR 253260 5 38,973,780 39,110,258 136.48 9 30.77% SCP2 SCP2 6342 1 53,165,536 53,289,870 124.33 18 50.00% SGK1 SGK1 6446 6 134,532,077 134,680,889 148.81 38 46.75% SGK2 SGK2 10110 20 41,621,100 41,647,687 26.59 9 34.62% SIRT1 SIRT1 23411 10 69,314,433 69,348,152 33.72 4 33.33% SIRT2 SIRT2 22933 19 44,061,040 44,082,201 21.16 7 38.89% SIRT3 SIRT3 23410 11 205,030 226,362 21.33 17 60.00% SKP2 SKP2 6502 5 36,187,946 36,219,904 31.96 15 51.72% SOCS1 SOCS1 8651 16 11,255,775 11,257,540 1.77 4 50.00% SOCS3 SOCS3 9021 17 73,864,457 73,867,753 3.30 4 50.00% MnSOD SOD2 6648 6 160,020,139 160,034,343 14.20 4 44.44% USP7 USP7 7874 16 8,893,452 8,964,842 71.39 12 42.11% 14-3-3 YWHAB 7529 20 42,947,758 42,970,575 22.82 6 50.00% YWHAE 7531 17 1,194,586 1,250,306 55.72 16 70.00% YWHAG 7532 7 75,794,044 75,826,278 32.23 5 35.71% YWHAH 7533 22 30,670,479 30,683,590 13.11 9 43.75% YWHAQ 10971 2 9,641,557 9,688,557 47.00 10 58.33% YWHAZ 7534 8 101,999,981 102,034,799 34.82 6 40.00% Total 1,023

Total

Chr Chromosome position of the gene according to NCBI Build 36, Start (bp) start position of the gene according to NCBI Build 36, End (bp) end position of the gene according to NCBI Build 36, Coverage coverage of genes based on Phased data HapMap II release 22 CEU, NA not available

Results

the shelterin complex (Vulliamy et al. 2008; Harrington et al. 1997; de Lange 2005) (Fig. 2). We analyzed SNPs within a 10-kb window around the selected genes (based on Pawlikowska et al. 2009) from genotyped GWAS data of 403 unrelated nonagenarian participants from the LLS and 1,670 middle-aged controls from the RS (Deelen et al. 2011). A description of the investigated samples is given in Table S1. In total, 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes were analyzed (Tables 1, 2, S3A, and S3B).