supplemental materials a genome-wide …...supplemental materials a genome-wide association study...

SUPPLEMENTAL MATERIALS

A genome-wide association study identifies 2 new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese

Zhibin Hu, Chen Wu, Yongyong Shi, Huan Guo, Xueying Zhao, Zhihua Yin, Lei Yang, Juncheng Dai, Lingmin Hu, Wen Tan, Zhiqiang Li, Qifei

Deng, Jiucun Wang, Wei Wu, Guangfu Jin, Yue Jiang, Dianke Yu, Guoquan Zhou, Hongyan Chen, Peng Guan, Yijiang Chen, Yongqian Shu, Lin Xu,

Xiangyang Liu, Li Liu, Pin Xu, Baohui Han, Chunxue Bai, Yuxia Zhao, Haibo Zhang, Ying Yan, Hongxia Ma, Jiaping Chen, Mingjie Chu, Feng Lu,

Feng Chen, Li Jin, Jiachun Lu, Baosen Zhou, Daru Lu, Tangchun Wu, Dongxin Lin & Hongbing Shen

Nature Genetics: doi:10.1038/ng.875

Supplementary Fig. 1: Plot of the first two components derived from a principle component based analysis implemented in the software package EIGENSTRAT. Four samples (BJ361, BJ631, jd1323 and n928) were outliers.

n928

jd1323 BJ361

BJ631


Supplementary Fig. 2: Plots of the first two components derived from a principle component based analysis implemented in the software package EIGENSTRAT. (a) Nanjing Study samples; (b) Beijing Study samples; (c) all GWAS scan samples. These plots suggest minimal evidence of population stratification. A set of 571,000 SNPs used in this analysis.

(a)

(b)

(c)


Supplementary Fig. 3: Quantile-Quantile plot of P-values in -log10 scale.

λ=1.050


Supplementary Fig. 4: Stratification analyses of the associations between lung cancer risk and the six SNPs. Each box and horizontal line represents the OR and 95% CI derived from the additive model. SC, squamous cell carcinoma; AC, adenocarcinoma; SCC, small cell carcinoma; other includes large cell lung cancer and mixed cell carcinoma. P values are from heterogeneity tests based on chi-squared based Q test.


Supplementary Table 1. Summary description of the samples used in this study GWAS scan

The Nanjing Study The Beijing Study Validation I Validation II

Variables Case

(n=1473) Control (n=1962)

Case (n=858)

Control (n=1115)

Case (n=2283)

Control (n=2243)

Case (n=4030)

Control (n=4166)

Age (Mean ± S.D.) 60.08±10.30 59.35±9.74 60.00±10.23 62.45±9.18 59.11±9.98 56.51±12.61 59.43±11.19 58.78±11.41 Gender

Male 1057 1214 654 872 1569 1525 2630 2651 Female 416 748 204 243 714 718 1400 1515

Smoking Status Current Smokers 741 636 511 447 1119 800 1602 1384 Former smokers 168 83 86 143 266 34 587 330 Never smokers 564 1243 261 525 898 1409 1841 2452

Smoking Levels (Mean ± S.D.) 41.43±26.86 30.96±20.28 44.81±29.64 32.35±19.88 40.25±25.51 26.20±18.70 37.17±25.34 24.53±18.18 ≤ 25(Pack-years) 254 327 166 232 425 455 774 1061 > 25(Pack-years) 655 392 431 358 960 379 1415 653

Histology Squamous cell carcinoma 421 401 822 1401

Adenocarcinoma 896 408 1153 1911 Small cell carcinoma 129 49 145 464

Other a 27 0 163 254 a Other includes large cell lung cancer and mixed cell carcinoma.


Supplementary Table 2. Associations of the 18 fast-track replicated SNPs and 3 additional selected SNPs from the GWAS scan MAF a Chr.

(cytoband) SNP Associated Gene MajorAllele Case Control

OR_all b P_all c P_all d OR_nj b P_nj b OR_bj b P_bj b

1p32.3 rs4927136 HNRPA1L-2 G 0.307 0.263 1.24 8.11×10-7 1.26×10-3 1.23 1.37×10-4 1.26 1.68×10-3 3q13.2 rs1846594 BOC T 0.346 0.225 1.78 2.71×10-40 8.58×10-37 1.80 1.05×10-27 1.75 2.38×10-14 5p15.33 rs465498 CLPTM1L A 0.125 0.159 0.76 9.56×10-7 2.35×10-7 0.77 2.19×10-4 0.74 1.11×10-3 6q14.1 rs9343676 IRAK1BP1 C 0.101 0.072 1.44 1.46×10-7 1.46×10-8 1.47 7.24×10-6 1.37 5.35×10-3 6p21.33 rs2523545 MICA T 0.150 0.106 1.48 1.96×10-11 1.13×10-3 1.41 2.41×10-6 1.59 1.18×10-6 6p21.33 rs4713447 HCG27 A 0.505 0.455 1.23 2.26×10-7 1.61×10-3 1.18 7.96×10-4 1.31 3.83×10-5 6p21.33 rs753725 GTF2H4 G 0.249 0.203 1.30 1.85×10-8 2.78×10-2 1.23 3.23×10-4 1.41 6.04×10-6 6p21.33 rs2517646 TRIM10 A 0.238 0.193 1.28 6.89×10-8 7.78×10-2 1.19 3.65×10-3 1.46 5.51×10-7 6p21.33 rs1419675 TRIM40 A 0.184 0.136 1.43 1.48×10-11 2.40×10-3 1.35 1.07×10-5 1.57 1.39×10-7 6p21.33 rs1632879 HLA-H A 0.105 0.073 1.47 1.10×10-8 3.15×10-2 1.42 3.65×10-5 1.59 5.52×10-5 6p21.33 rs407238 HLA-G G 0.202 0.163 1.29 2.48×10-7 9.83×10-2 1.19 5.50×10-3 1.48 1.52×10-6 6p22.3 rs2498274 LOC728643 G 0.137 0.105 1.34 5.25×10-7 8.14×10-3 1.29 7.09×10-4 1.43 1.60×10-4 8q12.1 rs2242154 CA8 G 0.361 0.409 0.82 7.36×10-7 8.34×10-5 0.84 3.06×10-4 0.79 6.24×10-4

11q12.2 rs174549 FADS1-FEN1 G 0.359 0.409 0.81 1.56×10-7 5.77×10-7 0.84 5.98×10-4 0.76 3.54×10-5 12q13.11 rs2956467 ANP32A C 0.248 0.177 1.48 3.77×10-17 5.46×10-14 1.23 5.55×10-4 1.97 6.60×10-19 13q12.12 rs753955 MIPEP-TNFRSF19 T 0.328 0.283 1.24 3.54×10-7 5.55×10-7 1.19 1.45×10-3 1.34 2.68×10-5 22q12.2 rs17728461 HORMAD2-LIF C 0.217 0.166 1.39 4.32×10-11 3.15×10-11 1.23 1.08×10-3 1.67 1.86×10-10 22q12.2 rs36600 MTMR3-HORMAD2 G 0.117 0.086 1.41 1.60×10-7 1.29×10-7 1.32 1.85×10-3 1.53 1.40×10-5

3q28 rs10937405 TP63 G 0.281 0.310 0.87 1.06×10-3 3.81×10-2 0.87 1.30×10-2 0.86 3.03×10-2 3q28 rs4488809 TP63 T 0.520 0.474 1.20 2.61×10-6 4.45×10-5 1.23 2.43×10-5 1.15 2.73×10-2 5p15.33 rs2736100 TERT A 0.453 0.415 1.17 5.54×10-5 1.52×10-6 1.15 5.64×10-3 1.22 2.52×10-3

a MAF, Minor allele-frequency. b OR_all: OR for the all samples in GWAS scan; OR_nj, P_nj : OR and P values for the Nanjing study samples in GWAS scan; OR_bj, P_bj : OR and P values for the Beijing study samples in GWAS scan. c P_all: P for the all samples in GWAS scan without PCs adjustment; d P_all: P for the all samples in GWAS scan with PCs adjustment.


Supplementary Table 3. SNPs reached the validation criteria but in highly linkage disequilibrium (r2 > 0.8) with selected replication SNPs Chr. SNP OR P value Replicated SNPs r2

6 rs1655902 1.45 4.59×10-8 rs1632879 0.996 rs2257914 1.33 2.94×10-7 rs1419675 0.856 rs2596571 1.41 4.70×10-9 rs2523545 0.946 rs2596573 1.40 5.56×10-9 rs2523545 0.936 rs7762933 1.22 4.88×10-7 rs4713447 1.0011 rs174534 0.82 7.68×10-7 rs174549 0.9511 rs174548 0.81 1.66×10-7 rs174549 1.0011 rs174570 0.82 8.14×10-7 rs174549 0.9511 rs174577 0.81 2.10×10-7 rs174549 0.9611 rs174583 0.81 2.20×10-7 rs174549 0.9411 rs4246215 0.82 9.35×10-7 rs174549 0.9722 rs2051764 1.40 2.82×10-7 rs36600 0.9822 rs737909 1.39 3.50×10-7 rs36600 0.9822 rs9614162 1.38 1.76×10-10 rs17728461 0.93


Supplementary Table 4. Associations of 21 SNPs in GWAS scan and validations MAF c SNPs Chr.

(cytoband) Study Cases b Controls b Cases Controls

ORadd (95% CI) d Padd

d

rs4927136 1p32.3 GWAS 222/982/1122 212/1191/1665 0.307 0.263 1.23(1.13-1.34) 4.1×10-6 G/A a Replication I 180/937/1131 180/861/1193 0.288 0.273 1.06(0.97-1.17) 2.1×10-1 rs1846594 3q13.2 GWAS 322/962/1039 151/1069/1828 0.346 0.225 1.79(1.63-1.95) 1.7×10-37 T/C a Replication I 115/789/1362 113/798/1318 0.225 0.230 0.99(0.89-1.10) 8.4×10-1 rs10937405 3q28 GWAS 185/919/1190 264/1288/1374 0.281 0.310 0.85(0.78-0.93) 2.9×10-4 C/T a Replication I 171/909/1181 218/922/1090 0.277 0.304 0.85(0.77-0.94) 9.9×10-4 Replication II 322/1551/2089 367/1710/2039 0.277 0.297 0.88(0.82-0.95) 5.8×10-4 Combined All 678/3379/4460 849/3920/4503 0.278 0.303 0.86(0.82-0.91) 2.1×10-9 rs4488809 3q28 GWAS 624/1175/531 692/1534/850 0.480 0.474 1.23(1.13-1.33) 4.6×10-7 T/C a Replication I 593/1151/523 485/1107/636 0.485 0.466 1.25(1.15-1.37) 6.1×10-7 Replication II 1097/2062/813 954/2023/1135 0.464 0.478 1.29(1.21-1.38) 6.0×10-15 Combined All 2314/4388/1867 2131/4664/2621 0.474 0.474 1.26(1.21-1.32) 7.2×10-26 rs465498 5p15.33 GWAS 31/517/1774 90/793/2187 0.125 0.158 0.73(0.65-0.82) 1.3×10-7 A/G a Replication I 39/513/1719 59/630/1536 0.130 0.168 0.70(0.61-0.79) 1.8×10-8 Replication II 88/973/2954 158/1147/2844 0.143 0.176 0.77(0.71-0.84) 2.9×10-9 Combined All 158/2003/6447 307/2570/6567 0.135 0.169 0.75(0.71-0.80) 1.2×10-20 rs2736100 5p15.33 GWAS 455/1196/672 538/1460/1061 0.453 0.415 1.18(1.09-1.28) 5.1×10-5 A/C a Replication I 484/1121/665 357/1126/751 0.460 0.412 1.25(1.15-1.37) 8.0×10-7 Replication II 933/1977/1056 719/1947/1419 0.484 0.414 1.34(1.26-1.43) 1.9×10-19 Combined All 1872/4294/2393 1614/4533/3231 0.470 0.414 1.27(1.22-1.33) 1.0×10-27 rs9343676 6q14.1 GWAS 36/393/1876 18/402/2636 0.101 0.072 1.48(1.29-1.70) 4.1×10-8 C/T a Replication I 12/306/1951 11/309/1912 0.073 0.074 0.98(0.83-1.16) 8.1×10-1 rs2523545 6p21.33 GWAS 60/575/1688 41/563/2452 0.150 0.106 1.47(1.31-1.65) 1.7×10-10 T/C a Replication I 50/610/1623 50/568/1625 0.155 0.149 1.09(0.97-1.24) 1.6×10-1 rs4713447 6p21.33 GWAS 574/1163/551 608/1540/882 0.495 0.455 1.21(1.12-1.31) 3.4×10-6 A/G a Replication I 566/1074/643 477/1161/605 0.483 0.471 1.09(1.00-1.19) 6.2×10-2 rs753725 6p21.33 GWAS 155/849/1326 124/1000/1952 0.249 0.203 1.29(1.17-1.41) 2.1×10-7 G/A a Replication I 156/877/1235 113/768/1346 0.262 0.223 1.32(1.19-1.46) 2.0×10-7 Replication II 227/1278/2408 230/1322/2540 0.221 0.218 1.01(0.94-1.09) 8.2×10-1 Combined All 538/3004/4969 467/3090/5838 0.240 0.214 1.15(1.10-1.21) 4.1×10-8 rs2517646 6p21.33 GWAS 149/808/1371 146/898/2033 0.238 0.193 1.28(1.16-1.40) 3.9×10-7 A/G a Replication I 165/887/1220 105/746/1381 0.268 0.214 1.41(1.27-1.57) 6.9×10-11 Replication II 245/1279/2468 261/1381/2497 0.222 0.230 0.95(0.88-1.02) 1.7×10-1 Combined All 559/2974/5059 512/3025/5911 0.238 0.214 1.14(1.08-1.20) 2.7×10-7


rs1419675 6p21.33 GWAS 87/675/1540 67/696/2299 0.184 0.136 1.42(1.27-1.58) 1.7×10-10 A/C a Replication I 96/740/1436 54/599/1578 0.205 0.158 1.44(1.28-1.62) 4.9×10-10 Replication II 129/972/2882 110/1071/2943 0.154 0.157 0.98(0.90-1.07) 6.1×10-1 Combined All 312/2387/5858 231/2366/6820 0.176 0.150 1.20(1.13-1.27) 3.6×10-10 rs1632879 6p21.33 GWAS 33/424/1870 20/410/2639 0.105 0.073 1.43(1.25-1.65) 3.6×10-7 A/G a Replication I 33/452/1759 33/413/1763 0.115 0.108 1.10(0.96-1.27) 1.6×10-1 rs407238 6p21.33 GWAS 105/728/1492 91/818/2166 0.202 0.163 1.29(1.16-1.43) 9.8×10-7 G/C a Replication I 138/797/1337 78/650/1499 0.236 0.181 1.48(1.32-1.65) 2.1×10-12 Replication II 152/1079/2727 152/1169/2798 0.175 0.179 0.98(0.91-1.07) 6.8×10-1 Combined All 395/2604/5556 321/2637/6463 0.198 0.174 1.18(1.12-1.25) 2.6×10-9 rs2498274 6p22.3 GWAS 64/504/1736 36/561/2429 0.137 0.105 1.35(1.20-1.52) 9.7×10-7 G/T a Replication I 44/560/1679 42/527/1674 0.142 0.136 1.13(1.00-1.29) 5.6×10-2 rs2242154 8q12.1 GWAS 315/1053/961 519/1475/1081 0.361 0.409 0.81(0.75-0.88) 7.3×10-7 C/T a Replication I 292/1031/934 330/1047/842 0.358 0.385 0.90(0.83-0.99) 3.1×10-2 Replication II 524/1823/1660 608/1864/1676 0.358 0.371 0.95(0.89-1.01) 9.5×10-2 Combined All 1131/3907/3555 1457/4386/3599 0.359 0.387 0.89(0.85-0.93) 2.0×10-7 rs174549 11q12.2 GWAS 301/1071/959 512/1489/1074 0.359 0.409 0.81(0.74-0.88) 1.0×10-7 G/A a Replication I 235/996/1036 355/1041/838 0.323 0.392 0.72(0.65-0.78) 1.4×10-12 Replication II 465/1704/1841 491/1798/1868 0.328 0.334 0.98(0.91-1.04) 4.8×10-1 Combined All 1001/3771/3836 1358/4328/3780 0.335 0.372 0.85(0.81-0.89) 7.6×10-13 rs2956467 12q13.11 GWAS 182/775/1344 113/823/2023 0.248 0.177 1.47(1.34-1.62) 2.9×10-15 C/G a Replication I 1468/723/78 1442/702/89 0.194 0.197 1.03(0.92-1.15) 5.9×10-1 rs753955 13q12.12 GWAS 247/1037/1047 238/1259/1568 0.328 0.283 1.24(1.14-1.35) 1.4×10-6 T/C a Replication I 250/1038/978 218/956/1061 0.339 0.311 1.11(1.01-1.23) 2.4×10-2 Replication II 429/1742/1825 306/1763/2038 0.325 0.289 1.18(1.11-1.27) 1.8×10-6 Combined All 926/3817/3850 762/3978/4667 0.330 0.292 1.18(1.13-1.24) 1.5×10-12 rs17728461 22q12.2 GWAS 109/787/1424 83/851/2126 0.217 0.166 1.35(1.22-1.49) 8.7×10-9 C/G a Replication I 115/807/1344 99/671/1463 0.229 0.195 1.25(1.12-1.39) 4.6×10-5 Replication II 169/1334/2439 170/1289/2669 0.212 0.197 1.09(1.01-1.18) 2.8×10-2 Combined All 393/2928/5207 352/2811/6258 0.218 0.187 1.20(1.14-1.27) 1.1×10-11 rs36600 22q12.2 GWAS 32/473/1798 19/485/2540 0.117 0.086 1.38(1.21-1.58) 2.2×10-6 G/A a Replication I 58/510/1708 31/383/1827 0.138 0.099 1.43(1.25-1.64) 1.7×10-7 Replication II 60/754/3193 57/692/3407 0.109 0.097 1.15(1.04-1.28) 5.7×10-3 Combined All 150/1737/6699 107/1560/7774 0.119 0.094 1.29(1.20-1.38) 6.2×10-13 a Major/minor alleles; b Variant homozygote/Heterozygote/Wild type homozygote; c MAF, Minor allele frequency; d Adjusted by age, gender and pack-year of smoking.


Supplementary Table 5. Haplotype analysis on 5p15.33 (rs465498 & rs2736100) and 22q12.2 (rs17728461 & rs36600) SNPs Frequency (%) Group Haplotype

Cases Controls OR(95%CI) b P b

5p15.33: rs465498 A/G a & rs2736100 A/C a 1 AA 42.72 45.17 1.00(ref.) 2 AC 43.86 38.05 1.23(1.18-1.19) <0.0001 3 GA 10.39 13.50 0.79(0.74-0.85) <0.0001 4 GC 3.03 3.28 0.96(0.85-1.09) 0.570

22q12.2: rs17728461 C/G a & rs36600 G/A a 1 CG 75.47 79.03 1.00(ref.) 2 GG 12.72 11.62 1.14(1.06-1.21) <0.0001 3 GA 9.15 6.99 1.37(1.26-1.48) <0.0001 4 CA 2.66 2.36 1.18(1.03-1.36) 0.016

a Major/minor alleles. b Adjusted by age, gender and pack-year of smoking.


Supplementary Table 6. SNPs identified by GWAS genotyping or imputation analyses at chromosomes 3q28, 5p15.33, 13q12.12 and 22q12.2 and their associations with lung cancer (P <1.0×10-4)

MAF Chr. SNP Position Minor Allele

Major Allele Cases Controls

P b ORadd Padd Identification by

3 rs4488809 190838963 T C 0.52 0.47 1.00 1.20 2.60E-06 Genotyping 3 rs7636839 190839643 A G 0.52 0.47 1.00 1.20 2.60E-06 Genotyping 5 rs2736100 1339516 C A 0.45 0.41 0.35 1.17 5.50E-05 Genotyping 5 rs4975615 1368343 G A 0.13 0.16 0.50 0.78 1.50E-05 Genotyping 5 rs4975616 1368660 G A 0.13 0.16 0.46 0.78 1.30E-05 Imputation 5 rs451360 1372680 A C 0.05 0.07 0.26 0.69 6.60E-05 Imputation 5 rs466502 1378767 G A 0.13 0.16 0.20 0.77 2.50E-06 Genotyping 5 rs465498 1378803 G A 0.13 0.16 0.18 0.77 3.20E-06 Genotyping 5 rs452932 1383253 C T 0.12 0.15 0.77 0.75 2.20E-06 Imputation 5 rs452384 1383840 C T 0.12 0.15 1.00 0.76 5.70E-06 Imputation 5 rs467095 1389221 C T 0.12 0.15 1.00 0.76 6.30E-06 Imputation 5 rs31484 1390906 T A 0.11 0.14 0.88 0.78 3.80E-05 Imputation 5 rs31489 1395714 A C 0.11 0.14 0.94 0.78 5.30E-05 Imputation 5 rs27070 1399303 C G 0.11 0.14 0.69 0.78 6.00E-05 Imputation

13 rs2861539 23187783 G A 0.32 0.28 0.69 1.19 5.70E-05 Imputation 13 rs12867512 23187849 A G 0.32 0.28 0.69 1.19 5.20E-05 Imputation 13 rs11617518 23188267 T C 0.32 0.28 0.69 1.19 4.60E-05 Imputation 13 rs9580741 23188621 C T 0.32 0.28 0.69 1.19 4.00E-05 Imputation 13 rs745068 23189878 G T 0.32 0.28 0.69 1.19 4.00E-05 Genotyping 13 rs745069 23189972 C T 0.33 0.29 0.79 1.20 1.90E-05 Imputation 13 rs2840252 23190701 A T 0.34 0.38 0.44 0.85 8.10E-05 Imputation 13 rs9553037 23191053 C T 0.31 0.35 0.84 0.84 2.60E-05 Imputation 13 rs753955 23191859 G A 0.33 0.29 0.83 1.20 2.00E-05 Genotyping 13 rs753954 23192105 A G 0.33 0.29 0.83 1.19 3.00E-05 Imputation 22 rs2349225 28518102 A T 0.11 0.08 0.80 1.37 3.40E-06 Imputation 22 rs36578 28536066 A G 0.11 0.08 0.91 1.34 7.30E-06 Imputation 22 rs1076137 28548545 A G 0.10 0.08 1.00 1.32 3.40E-05 Imputation 22 rs3958025 28553953 C G 0.10 0.08 1.00 1.32 3.30E-05 Genotyping 22 rs5752968 28558000 A G 0.10 0.08 1.00 1.32 3.30E-05 Imputation 22 rs4993442 28577810 G T 0.11 0.08 1.00 1.38 1.50E-06 Imputation 22 rs9625874 28613179 G A 0.11 0.08 0.90 1.39 1.00E-06 Imputation 22 rs3887275 28624666 G C 0.11 0.08 0.73 1.40 2.40E-07 Imputation 22 rs8136147 28628788 T C 0.11 0.08 0.73 1.40 2.40E-07 Imputation


22 rs4823063 28633334 C G 0.11 0.08 1.00 1.39 9.20E-07 Imputation 22 rs36590 28652624 T C 0.12 0.08 0.91 1.40 2.10E-07 Imputation 22 rs36594 28658936 C T 0.12 0.08 0.91 1.40 2.10E-07 Imputation 22 rs36604 28664692 C A 0.11 0.08 1.00 1.39 9.20E-07 Imputation 22 rs36605 28664910 A T 0.12 0.08 0.91 1.40 2.20E-07 Imputation 22 rs36606 28664964 A T 0.11 0.08 1.00 1.39 9.60E-07 Imputation 22 rs36609 28669011 T G 0.12 0.08 0.91 1.40 2.20E-07 Imputation 22 rs737904 28673206 A T 0.11 0.08 1.00 1.38 1.10E-06 Genotyping 22 rs5763634 28675086 T C 0.11 0.08 1.00 1.38 1.10E-06 Imputation 22 rs5763640 28677806 A T 0.11 0.08 1.00 1.38 1.10E-06 Imputation 22 rs5763644 28680230 G A 0.11 0.08 1.00 1.38 1.10E-06 Imputation 22 rs2051764 28686435 G A 0.12 0.08 0.91 1.40 2.50E-07 Genotyping 22 rs4239932 28692938 T G 0.11 0.08 1.00 1.39 8.30E-07 Imputation 22 rs2017677 28707816 G C 0.12 0.08 0.91 1.40 2.10E-07 Imputation 22 rs737909 28713312 T G 0.12 0.08 0.91 1.40 2.10E-07 Genotyping 22 rs3788423 28715544 T C 0.12 0.09 1.00 1.41 1.50E-07 Imputation 22 rs2412963 28715835 G A 0.12 0.09 1.00 1.41 1.50E-07 Imputation 22 rs41172 28747419 C T 0.08 0.05 0.60 1.59 1.50E-09 Imputation 22 rs28257 28753669 G A 0.07 0.05 0.55 1.56 6.50E-08 Imputation 22 rs41175 28756691 C T 0.08 0.05 0.60 1.59 1.40E-09 Imputation 22 rs41178 28765087 A G 0.08 0.05 0.60 1.59 1.40E-09 Imputation 22 rs41179 28766231 G A 0.08 0.05 0.60 1.59 1.40E-09 Imputation 22 rs193473 28772953 G A 0.12 0.08 0.64 1.43 3.70E-08 Imputation 22 rs8141404 28798770 T C 0.12 0.08 0.64 1.43 4.70E-08 Imputation 22 rs7510705 28818472 G A 0.08 0.05 0.60 1.58 3.00E-09 Imputation 22 rs9625919 28825512 T G 0.12 0.08 0.64 1.43 4.70E-08 Imputation 22 rs6006356 28827725 A G 0.31 0.27 0.36 1.19 4.70E-05 Imputation 22 rs718772 28828761 G A 0.12 0.08 0.82 1.41 9.80E-08 Imputation 22 rs4337577 28836682 C G 0.08 0.05 0.72 1.57 4.90E-09 Imputation 22 rs4239933 28836968 G C 0.12 0.08 0.73 1.42 7.50E-08 Imputation 22 rs11090598 28846324 G A 0.12 0.09 0.50 1.40 1.00E-07 Imputation 22 rs8139832 28862080 C T 0.31 0.28 0.34 1.18 9.20E-05 Imputation 22 rs36600 a 28667586 A G 0.12 0.09 1.00 1.40 2.51E-07 Genotyping 22 rs9620953 28870799 T C 0.09 0.06 0.52 1.49 1.30E-07 Imputation 22 rs9625933 28879770 A G 0.09 0.06 0.62 1.52 2.30E-08 Imputation 22 rs8141765 28886793 A C 0.09 0.06 0.62 1.52 1.90E-08 Imputation 22 rs8138286 28887541 C A 0.09 0.06 0.62 1.52 1.90E-08 Imputation


22 rs1978083 28894997 G C 0.08 0.05 0.58 1.60 2.00E-09 Imputation 22 rs12167333 28900366 T C 0.08 0.05 0.58 1.59 3.00E-09 Imputation 22 rs713875 28917041 C G 0.33 0.29 0.38 1.20 9.70E-06 Genotyping 22 rs9614157 28922364 G A 0.22 0.17 0.48 1.39 5.90E-11 Imputation 22 rs9614158 28922434 G A 0.09 0.06 0.52 1.59 3.20E-10 Imputation 22 rs17728461 28923106 G C 0.22 0.17 0.48 1.39 5.90E-11 Genotyping 22 rs2023683 28924150 A G 0.09 0.06 0.52 1.59 3.20E-10 Imputation 22 rs9614159 28925797 A G 0.21 0.17 0.24 1.38 2.00E-10 Imputation 22 rs9614162 28928656 A G 0.21 0.16 0.09 1.39 9.60E-11 Genotyping

a Not included in HapMap phase II, imputed by using 1000 genome data. b P values for Hardy-Weinberg Equilibrium in controls.


Supplementary Table 7. Stratification analysis on the 6 SNPs rs4488809 rs465498 rs2736100

Variables Cases a Controls a OR (95% CI) b P b Cases a Controls a OR (95% CI) b P b Cases a Controls a OR (95% CI) b P b

Age

≤60 1223/2282/990 1168/2459/1374 1.22(1.15-1.29) 5.0E-11 74/1030/3414 152/1363/3492 0.73(0.67-0.80) 1.9E-13 995/2294/1214 865/2393/1719 1.29(1.22-1.37) 3.9E-17

>60 1091/2106/877 963/2205/1247 1.32(1.24-1.41) 5.4E-17 84/973/3033 155/1207/3075 0.77(0.71-0.85) 9.5E-09 877/2000/1179 749/2140/1512 1.26(1.18-1.34) 3.7E-12

Gender

Male 1561/2995/1308 1408/3079/1727 1.25(1.18-1.32) 9.4E-16 98/1389/4397 204/1684/4340 0.75(0.69-0.80) 2.1E-14 1212/2946/1695 1057/2987/2141 1.23(1.17-1.30) 3.6E-14

Female 753/1393/559 723/1585/894 1.29(1.20-1.39) 8.5E-12 60/614/2050 103/886/2227 0.76(0.69-0.84) 1.1E-07 660/1348/698 557/1546/1090 1.36(1.26-1.46) 4.3E-16

Smoking status

Current 1029/2003/915 728/1586/931 1.21(1.13-1.30) 1.4E-08 61/940/2953 108/883/2258 0.76(0.70-0.84) 9.1E-09 829/1944/1168 555/1553/1121 1.21(1.13-1.29) 2.1E-08

Former 305/556/233 135/303/150 1.21(1.04-1.39) 1.1E-02 25/259/819 31/169/389 0.68(0.57-0.82) 4.9E-05 210/546/329 106/274/206 1.13(0.98-1.30) 9.7E-02

Never 980/1829/719 1268/2775/1540 1.29(1.21-1.37) 5.5E-16 72/804/2675 168/1518/3920 0.78(0.72-0.85) 1.1E-08 833/1804/896 953/2706/1904 1.36(1.28-1.45) 3.3E-23

Smoking level

≤25 444/839/318 467/1024/568 1.30(1.18-1.43) 5.0E-08 23/357/1229 77/540/1453 0.72(0.63-0.82) 6.7E-07 325/844/439 352/966/731 1.27(1.16-1.40) 6.3E-07

>25 890/1720/830 396/865/513 1.18(1.09-1.28) 4.5E-05 63/842/2543 62/512/1194 0.74(0.66-0.83) 8.1E-08 714/1646/1058 309/861/596 1.14(1.05-1.24) 1.8E-03

Histology

SC 786/1545/690 2131/4664/2621 1.24(1.16-1.32) 1.1E-10 43/707/2283 307/2570/6567 0.72(0.66-0.79) 4.1E-12 613/1508/896 1614/4533/3231 1.21(1.14-1.29) 6.0E-09

AC 1240/2205/882 2131/4664/2621 1.32(1.25-1.39) 4.2E-25 89/994/3267 307/2570/6567 0.76(0.70-0.82) 1.2E-13 1020/2155/1148 1614/4533/3231 1.33(1.26-1.40) 3.1E-26

SCC 174/408/200 2131/4664/2621 1.05(0.94-1.16) 3.9E-01 15/195/573 307/2570/6567 0.80(0.69-0.93) 3.4E-03 144/405/231 1614/4533/3231 1.14(1.02-1.27) 1.6E-02

Other 114/230/95 2131/4664/2621 1.23(1.07-1.41) 3.1E-03 11/107/324 307/2570/6567 0.82(0.68-0.99) 4.1E-02 95/226/118 1614/4533/3231 1.27(1.11-1.46) 5.8E-04

Area

GWAS 624/1175/531 692/1534/850 1.23(1.13-1.33) 4.6E-07 31/517/1774 90/793/2187 0.73(0.65-0.82) 1.3E-07 455/1196/672 538/1460/1061 1.18(1.09-1.28) 5.1E-05

Southern 936/1748/782 756/1725/938 1.27(1.19-1.37) 2.9E-11 52/765/2655 88/936/2402 0.70(0.63-0.78) 1.2E-11 765/1726/985 546/1638/1220 1.33(1.23-1.42) 1.0E-14

Northern 754/1465/554 683/1405/833 1.29(1.20-1.40) 5.0E-11 75/721/2018 129/841/1978 0.80(0.72-0.88) 7.8E-06 652/1372/736 530/1435/950 1.29(1.20-1.40) 5.3E-11 a Variant homozygote/Heterozygote/Wild type homozygote; b Adjusted by age, gender and pack-year of smoking where is appropriate.


Supplementary Table 7. Stratification analysis on the 6 SNPs (cont.) rs753955 rs17728461 rs36600

Variables Cases a Controls a OR (95% CI) b P b Cases a Controls a OR (95% CI) b P b Cases a Controls a OR (95% CI) b P b

Age ≤60 512/1994/2007 396/2105/2490 1.24(1.16-1.32) 5.2E-11 206/1518/2752 197/1482/3330 1.19(1.11-1.28) 2.2E-06 85/895/3527 59/791/4163 1.32(1.20-1.45) 6.8E-09

>60 414/1823/1843 366/1873/2177 1.12(1.05-1.20) 1.1E-03 187/1410/2455 155/1329/2928 1.22(1.13-1.32) 1.0E-06 65/842/3172 48/769/3611 1.25(1.13-1.39) 1.2E-05

Gender

Male 621/2639/2613 496/2622/3091 1.19(1.13-1.27) 2.6E-09 267/1976/3583 235/1831/4152 1.19(1.12-1.27) 2.3E-07 108/1204/4555 74/1047/5117 1.30(1.19-1.41) 2.1E-09

Female 305/1178/1237 266/1356/1576 1.17(1.08-1.26) 1.2E-04 126/952/1624 117/980/2106 1.23(1.12-1.34) 8.4E-06 42/533/2144 33/513/2657 1.28(1.13-1.44) 6.0E-05

Smoking status

Current 427/1786/1737 239/1377/1623 1.26(1.17-1.35) 7.9E-10 180/1325/2420 124/998/2120 1.15(1.06-1.25) 9.5E-04 77/809/3058 42/524/2686 1.33(1.19-1.48) 1.6E-07

Former 118/464/517 50/257/276 1.06(0.91-1.24) 4.6E-01 46/378/659 18/164/398 1.33(1.11-1.60) 2.3E-03 17/232/852 6/90/494 1.44(1.13-1.83) 2.8E-03

Never 381/1567/1596 473/2344/2768 1.17(1.10-1.25) 2.0E-06 167/1225/2128 210/1649/3740 1.24(1.15-1.34) 9.7E-09 56/696/2789 59/946/4594 1.24(1.12-1.37) 1.5E-05

Smoking level

≤25 170/718/723 162/884/1005 1.18(1.06-1.30) 1.7E-03 79/517/995 76/641/1337 1.13(1.01-1.27) 3.9E-02 27/332/1249 25/351/1690 1.26(1.09-1.46) 1.8E-03

>25 375/1532/1531 127/750/894 1.26(1.15-1.37) 6.5E-07 147/1186/2084 66/521/1181 1.22(1.10-1.35) 1.5E-04 67/709/2661 23/263/1490 1.44(1.26-1.65) 9.4E-08

Histology

SC 322/1355/1348 762/3978/4667 1.19(1.11-1.28) 6.6E-07 156/1029/1810 352/2811/6258 1.24(1.15-1.35) 3.8E-08 63/632/2329 107/1560/7774 1.37(1.24-1.51) 4.8E-10

AC 473/1938/1934 762/3978/4667 1.20(1.13-1.27) 3.9E-10 187/1468/2667 352/2811/6258 1.17(1.10-1.25) 2.3E-06 67/848/3428 107/1560/7774 1.23(1.14-1.34) 6.7E-07

SCC 73/348/361 762/3978/4667 1.12(0.99-1.25) 6.2E-02 34/276/464 352/2811/6258 1.24(1.09-1.41) 1.0E-03 12/175/591 107/1560/7774 1.45(1.24-1.70) 4.3E-06

Other 58/176/207 762/3978/4667 1.20(1.04-1.39) 1.5E-02 16/155/266 352/2811/6258 1.18(1.00-1.39) 5.2E-02 8/82/351 107/1560/7774 1.22(0.99-1.52) 6.4E-02

Area

GWAS 247/1037/1047 238/1259/1568 1.24(1.14-1.35) 1.4E-06 109/787/1424 83/851/2126 1.35(1.22-1.49) 8.7E-09 32/473/1798 19/485/2540 1.38(1.21-1.58) 2.2E-06

Southern 413/1593/1470 325/1509/1601 1.15(1.07-1.24) 3.0E-04 207/1267/1982 166/1147/2124 1.16(1.06-1.26) 7.0E-04 78/814/2576 60/693/2692 1.21(1.09-1.35) 2.5E-04

Northern 266/1187/1333 199/1210/1498 1.16(1.07-1.26) 6.2E-04 77/874/1801 103/813/2008 1.10(0.99-1.21) 6.7E-02 40/450/2325 28/382/2542 1.28(1.12-1.46) 3.1E-04 a Variant homozygote/Heterozygote/Wild type homozygote; b Adjusted by age, gender and pack-year of smoking where is appropriate. SC, squamous cell carcinoma; AC, adenocarcinoma; SCC, small cell carcinoma; other includes large cell lung cancer and mixed cell carcinoma.


Supplementary Table 8. Associations of other reported common susceptibility loci of lung cancer identified by previous GWAS studies MAF c SNP Chr.

(cytoband) Position a Associated gene

Minorallele CEU b CHB b Cases Controls

P d ORadd (95% CI) P_add Ref.

rs7626795 3q28 191833155 IL1RAP G 0.13 0.20 0.189 0.180 0.58 1.06(0.96-1.17) 2.79×10-1 3 rs401681 5p15.33 1375087 CLPTM1L T 0.43 0.29 0.303 0.323 0.27 0.91(0.84-0.99) 2.10×10-2 5, 8, 11 rs938682 15q25.1 76683602 CHRNA3 G 0.18 0.53 0.422 0.432 0.58 0.96(0.89-1.04) 3.17×10-1 8, 11 rs6080100 20p12.1 15951406 MACROD2 C 0.35 0.10 0.089 0.073 0.59 1.24(1.08-1.43) 2.39×10-3 2

a Based on NCBI build 36; b Based on Hapmap Phase II data; c MAF, Minor allele frequency; d P values for Hardy-Weinberg Equilibrium in controls.


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