GWAS
Region SNPs
N SNP rs number** Local loci*** References
1q23.2 1 rs2808630* CRP [1]
2p13.3 1 rs4254535 GKN2||GKN1 [2]
3p24.1 1 rs1530057 RBMS3 [2]
3q28 1 rs7626795 IL1RAP [1]
4q22.1 2 rs2869967 rs7671167* FAM13A [3]
4q31.21 7 rs2202507 rs12504628 rs13147758 rs1489759 rs1828591
rs1980057 rs13118928 [3-8]
5p15.33 13 rs2242652 rs2736100 rs2853676 rs2853668 rs2735845 rs4635969 rs4975616 rs1801075 rs7727912 rs451360 rs402710 rs401681 rs31489
TERT, CLPTM1L [2,9-11]
6p21.33 22 rs1052486 rs3117582 rs805297 rs805262 rs707974* rs7029 rs3117578 rs3115667 rs2280800 rs2295663 rs6916278 rs385306 rs805284 rs805293 rs805292 rs805304 rs3131382 rs3117572 rs2299851 rs3131379 rs707939 rs1802127
APOM, BAG6, C6orf47, CSNK2B, GPANK1, LY6G5C, ABHD16A, MIR4646, LY6G6F, LY6G6D, LY6G6E, C6orf25, LY6G6C, CLIC1, DDAH2, MSH5, SAPCD1
[2,9,11]
6p22.1 1 rs4324798 TRNAF-GAA||TRNAA-AGC [9]
10q23.31 1 rs1926203 ACTA2 [2]
13q31.3 1 rs2352028 GPC5 [12]
15q15.2 9 rs3917223 rs12050604 rs35985214 rs504417 rs11853991
rs748404 rs2602141 rs689647 rs560191 UBR1, TGM5, TP53BP1 [2,9,13]
15q25.1 17 rs13180 rs4362358 rs8034191 rs4461039 rs3885951 rs11858230 rs16969968 rs660652 rs12914385 rs12443170 rs8042374 rs1948 rs7178270 rs950776 rs12440014 rs11636753 rs1316971
IREB2, HYKK (previously LOC123688),
PSMA4, CHRNA5, CHRNA3, CHRNB4 [1,2,4,5,9,11, 14,15]
* Failed genotype assay (call rate <0.95) or Hardy-Weinberg equilibrium test (P<0.001).
** Bolded rs numbers signify SNPs identified by GWAS. The other rs numbers signify putatively functional SNPs or tagSNPs for genes in the GWAS-identified region. The tagSNPs capture common variants (minor allele frequency ≥0.05).
REFERENCES – Supplemental Table 1
1. Amos CI, Wu X, Broderick P, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008;40:616-22.
2. Broderick P, Wang Y, Vijayakrishnan J, et al. Deciphering the impact of common genetic variation on lung cancer risk: A genome-wide association study. Cancer Res 2009;69:6633- 41.
3. Hancock DB, Eijgelsheim M, Wilk JB, et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet 2010;42:45-52.
4. Cho MH, Boutaoui N, Klanderman BJ, et al. Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat Genet 2010;42:200-2.
5. Pillai SG, Ge D, Zhu G, et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): Identification of two major susceptibility loci. PLoS Genet 2009;5:e1000421.
6. Repapi E, Sayers I, Wain LV, et al. Genome-wide association study identifies five loci associated with lung function. Nat Genet 2010;42:36-44.
7. Wilk JB, Chen TH, Gottlieb DJ, et al. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet 2009;5:e1000429.
8. Young RP, Hopkins RJ, Whittington CF, Hay BA, Epton MJ, Gamble GD. Individual and cumulative effects of GWAS susceptibility loci in lung cancer: Associations after sub- phenotyping for COPD. PLoS One 2011;6:e16476.
9. Landi MT, Chatterjee N, Yu K, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 2009;85:679-91.
10. McKay JD, Hung RJ, Gaborieau V, et al. Lung cancer susceptibility locus at 5p15.33. Nat Genet 2008;40:1404-6.
11. Wang Y, Broderick P, Webb E, et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet 2008;40:1407-9.
12. Li Y, Sheu CC, Ye Y, et al. Genetic variants and risk of lung cancer in never smokers: A genome-wide association study. Lancet Oncol 2010;11:321-30.
13. Rafnar T, Sulem P, Besenbacher S, et al. Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk. Cancer Res 2011;71:1356-61.
14. Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008;452:633-7.
15. Liu P, Vikis HG, Wang D, et al. Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer. J Natl Cancer Inst 2008;100:1326-30.
2
smoking intensity
Risk factor Points
Duration of smoking, in years <30 -10
30-39 0
40-49 8
≥50 14
Age, in yearsa younger 0
older 4
Smoking statusb current 0
former -3
Smoking intensity, in cigarettes/day <20 -4
20-29 0
30-39 2
≥40 5
a Older age defined as age ≥57, ≥59, ≥61, and ≥68 years for persons smoking <30, 30-39, 40-49, and ≥50 years, respectively.
b The quit smoking category includes former smokers with current attained age at least one year greater than age quit
Supplemental Table 3: Characteristics of controls (N=1166) placed in high and low risk groupsa according to the two-SNP 5p15.33 classifier
High Risk Low Risk
N % N % Pc
N 428 100.0 738 100.0
Year 0.23
2002 104 24.3 211 28.6
2003 192 44.9 301 40.8
2004-2005 132 30.8 226 30.6
Sex 0.62
male 225 52.6 377 51.1
female 203 47.4 361 48.9
Age, in years 0.22
50-59 243 56.8 422 57.2
60-69 137 32.0 255 34.6
70-79 48 11.2 61 8.3
Family historyb 0.28
no 348 81.9 618 84.3
yes 77 18.1 115 15.7
Symptoms, N 0.19
0 152 35.5 237 32.1
1 110 25.7 221 29.9
2 96 22.4 181 24.5
3 70 16.4 99 13.4
Duration of
smoking, in years 0.25
<30 29 6.8 47 6.4
30-39 180 42.1 348 47.2
40-49 171 40.0 254 34.4
≥50 48 11.2 89 12.1
Cigarettes/day 0.20
<20 109 25.5 229 31.0
20-29 194 45.3 299 40.5
30-39 75 17.5 132 17.9
≥40 50 11.7 78 10.6
Pack-years 0.50
<35 98 22.9 194 26.3
35-49 108 25.2 192 26.0
50-64 117 27.3 181 24.5
≥65 105 24.5 171 23.2
COPD 0.81
no 343 80.1 587 79.5
yes 85 19.9 151 20.5
4
N % N % Pc
Emphysema 0.22
none 239 55.8 411 55.7
trace 73 17.1 155 21.0
mild 62 14.5 100 13.6
mod-severe 54 12.6 72 9.8
GOLD 0.89
no limitation 234 54.7 418 56.6
mild 60 14.0 105 14.2
moderate 102 23.8 163 22.1
severe 32 7.5 52 7.0
LEGEND: Symptoms – symptom (cough, phlegm, wheeze) count; COPD – doctor diagnosis of emphysema or bronchitis; GOLD – Global Initiative for Chronic Obstructive Lung Disease severity of airflow limitation.
a The High Risk group consisted of carriers of the rs7727912 minor allele and homozygotes for the rs2736100 common allele.
b First-degree relative with lung cancer (data missing in three high-risk and five low-risk controls).
c Differences in characteristics between high and low risk groups were assessed using Chi-square tests.
Supplemental Table 4: Characteristics of controls (N=1113) placed in high and low risk groupsa according to the two-SNP 6p21.33 classifierb
High Risk Low Risk
N % N % Pd
N 489 100.0 624 100.0
Year 0.34
2002 134 27.4 181 29.0
2003 228 46.6 264 42.3
2004-2005 127 26.0 179 28.7
Sex 0.13
male 241 49.3 336 53.8
female 248 50.7 288 46.2
Age, in years 0.69
50-59 282 57.7 360 57.7
60-69 157 32.1 209 33.5
70-79 50 10.2 55 8.8
Family historyc 0.83
no 409 84.2 518 83.7
yes 77 15.8 101 16.3
Symptoms, N 0.76
0 169 34.6 201 32.2
1 134 27.4 185 29.6
2 112 22.9 149 23.9
3 74 15.1 89 14.3
Duration of
smoking, in years 0.22
<30 39 8.0 35 5.6
30-39 223 45.6 284 45.5
40-49 165 33.7 237 38.0
≥50 62 12.7 68 10.9
Cigarettes/day 0.046
<20 128 26.2 192 30.8
20-29 199 40.7 271 43.4
30-39 97 19.8 102 16.3
≥40 65 13.3 59 9.5
Pack-years 0.32
<35 114 23.3 164 26.3
35-49 127 26.0 160 25.6
50-64 120 24.5 164 26.3
≥65 128 26.2 136 21.8
COPD 0.0014
no 368 75.3 518 83.0
yes 121 24.7 106 17.0
6
N % N % Pd
Emphysema 0.0088
none 261 53.4 355 56.9
trace 82 16.8 135 21.6
mild 83 17.0 75 12.0
mod-severe 63 12.9 59 9.5
GOLD 0.038
no limitation 266 54.4 355 56.9
mild 57 11.7 99 15.9
moderate 122 24.9 131 21.0
severe 44 9.0 39 6.3
LEGEND: Symptoms – symptom (cough, phlegm, wheeze) count; COPD – doctor diagnosis of emphysema or bronchitis; GOLD – Global Initiative for Chronic Obstructive Lung Disease severity of airflow limitation.
a The High Risk group consisted of carriers of the rs1802127 minor allele and the homozygotes for the rs805297 common allele.
b Fifty-three subjects could not be classified because of missing genotype data.
c First-degree relative with lung cancer (data missing in three high-risk and five low-risk controls).
d Differences in characteristics between high and low risk groups were assessed using Chi-square tests.
Supplemental Table 5: Characteristics of controls (N=1165) placed in high and low risk groupsa according to the two-SNP 15q25.1 classifierb
High Risk Low Risk
N % N % Pd
N 481 684
Year 0.66
2002 130 27.0 185 27.0
2003 210 43.7 283 41.4
2004-2005 141 29.3 216 31.6
Sex 0.12
male 235 48.9 366 53.5
female 246 51.1 318 46.5
Age, in years 0.34
50-59 281 58.4 383 56.0
60-69 162 33.7 230 33.6
70-79 38 7.9 71 10.4
Family historyc 0.59
no 402 84.1 563 82.9
yes 76 15.9 116 17.1
Symptoms, N 0.56
0 161 33.5 228 33.3
1 135 28.1 196 28.7
2 108 22.5 169 24.7
3 77 16.0 91 13.3
Duration of
smoking, in years 0.59
<30 36 7.5 40 5.8
30-39 222 46.2 305 44.6
40-49 169 35.1 256 37.4
≥50 54 11.2 83 12.1
Cigarettes/day 0.10
<20 123 25.6 215 31.4
20-29 206 42.8 286 41.8
30-39 91 18.9 116 17.0
≥40 61 12.7 67 9.8
Pack-years 0.038
<35 103 21.4 189 27.6
35-49 134 27.9 165 24.1
50-64 118 24.5 180 26.3
≥65 126 26.2 150 21.9
COPD 0.26
no 376 78.2 553 80.8
yes 105 21.8 131 19.2
Emphysema 0.0011
8
N % N % Pd
none 241 50.1 408 59.6
trace 100 20.8 128 18.7
mild 70 14.6 92 13.5
mod-severe 70 14.6 56 8.2
GOLD 0.63
no limitation 260 54.1 391 57.2
mild 68 14.1 97 14.2
moderate 114 23.7 151 22.1
severe 39 8.1 45 6.6
LEGEND: Symptoms – symptom (cough, phlegm, wheeze) count; COPD – doctor diagnosis of emphysema or bronchitis; GOLD – Global Initiative for Chronic Obstructive Lung Disease severity of airflow limitation.
a The High Risk group consisted of rs12440014 common allele homozygotes with one or two copies of the rs8034191 minor allele.
b One subject could not be classified because of missing genotype data.
c First-degree relative with lung cancer (data missing in three high-risk and five low-risk controls).
d Differences in characteristics between high and low risk groups were assessed using Chi-square tests.
Supplemental Figure 1: Decision trees
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