Figure S1. Quantile-quantile plot in –log10 scale for the individual studies The red line...
9
Figure S1. Quantile-quantile plot in –log10 scale for the individual studies The red line represents concordance of observed and expected values. The shaded area indicates 99% concentration band. (A) MD Anderson Cancer Center Lung Cancer GWAS. Inflation factor (λ) for 90% bottom SNPs = 1.02 ; (B) Liverpool Lung Project, λ= 1.14 ; (C) ICR-Lung Cancer GWA Study, λ= 1.03; (D) IARC GWAS, λ= 1.05; (E) DeCODE Genetics, λ= 1.06; (F) HGF Germany, λ= 1.05; (G) Harvard Lung Cancer Study, λ= 1.01; (H) NCI GWAS, λ= 1.02; (I) SLRI/Toronto Lung Cancer Study, λ= 1.05. (A) (B) (C) (D) (F) (E) (G) (H) (I)
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Transcript of Figure S1. Quantile-quantile plot in –log10 scale for the individual studies The red line...
Figure S1. Quantile-quantile plot in –log10 scale for the individual studiesThe red line represents concordance of observed and expected values. The shaded area indicates 99% concentration band.(A) MD Anderson Cancer Center Lung Cancer GWAS. Inflation factor (λ) for 90% bottom SNPs = 1.02 ; (B) Liverpool Lung Project, λ= 1.14 ; (C) ICR-Lung Cancer GWA Study, λ= 1.03; (D) IARC GWAS, λ= 1.05; (E) DeCODE Genetics, λ= 1.06; (F) HGF Germany, λ= 1.05; (G) Harvard Lung Cancer Study, λ= 1.01; (H) NCI GWAS, λ= 1.02; (I) SLRI/Toronto Lung Cancer Study, λ= 1.05.
(A) (B)
(C) (D)
(F)(E)
(G) (H)
(I)
Chromosome
-log
10(P
-val
ue)
(A)
Figure S2. Meta-analyses results: random effects model(A) Manhattan plot of P-values for the fixed effect model. Combined P values were derived from the per-allele model. Core 318,094 SNPs corresponding to the Illumina HumanHap 300 BeadChips array are shown at the Manhattan plots as round-shaped. Additional 217,914 SNPs corresponding to the Illumina HumanHap550 array are shown as triangle-shaped. (B) Quantile-quantile plot for P-values in –log10 scale for the fixed effect model for the core 318,094 SNPs. Inflation factor (λ) for the 90% bottom SNPs = 1.10. The red line represents concordance of observed and expected values. The shaded area indicates 99% concentration band.
-log10(expected P-value)
-log
10(O
bser
ved P
-val
ue)
B(B)
(A) Men
90% bottom λ =1.05
(B) Women
90% bottom λ = 1.03
(C) Never Smokers
90% bottom λ = 1.01
(D) Former Smokers
90% bottom λ = 1.03
(E) Current Smokers
90% bottom λ = 1.05
(F) Ever Smokers
90% bottom λ = 1.09
(H) Small cell carcinoma(G) Large cell carcinoma
90% bottom λ = 1.0 90% bottom λ = 1.03
(J) Later onset lung cancer
(K) Family History o f lung cancer
90% bottom λ = 1.07
(L) No Family History o f Lung Cancer
90% bottom λ = 1.06 90% bottom λ = 1.01
90% bottom λ = 1.04
(I) Early onset lung cancer
(M) Stage 1 and 2 (N) Stage 3 and 4
90% bottom λ = 1.02 90% bottom λ = 1.04
Figure S3. Manhattan plots for the meta-analysis by specific subgroups: fixed effect model Combined P values were derived from the per-allele model. Core 318,094 SNPs corresponding to the Illumina HumanHap 300 BeadChips array are shown at the Manhattan plots as round-shaped. Additional 217,914 SNPs corresponding to the Illumina HumanHap550 array are shown as triangle-shaped. Manhattan plots for adenocarcinoma and squamous cell carcinoma are presented in the Figure 1.
Figure S4. Regional plot of the 2q32 (A), 5p15 (B), 6p21-6p22 (C), 9p21 (D), 12p13 (E) and 15q25 (F) loci using imputed data.For the 9p21, 2q32.1, 6p22.3 and 12p13.33 loci results are presented for the squamous cell carcinoma histology. Results (-log10P) are shown for SNPs genotyped and imputed within the region. The most significant SNP in the locus are shown diamond-shaped and the r2 values for the rest of the SNPs are indicated by different colours depending on the LD level in CEU population. The genes within the region are annotated and shown as arrows.
(A) 2q32.1 (B) 5p15.33
(D) 9p21.3(C) 6p22.3-6p21.31
(E) 12p13.33 (F) 15q25.1
(A) (B)
(C) (D)
(E) (F)
Men
Women
Never
Current
Former
Adenocarcinoma
Squamous carcinoma
Small Cell Lung Cancer
<=50
>50
Overall (RSQR=0.45)
By Gender (Phet=0.41)
By Smoking (Phet=0.12)
By Histology (Phet=0.69)
By Age (Phet=0.66)
2,338
1,717
621
829
254
1,255
1,307
825
179
399
1,939
3,077
2,084
993
1,266
226
1,585
3,077
3,077
3,077
442
2,635
0.44
0.24
0.82
0.66
0.12
0.12
0.75
0.18
0.77
0.50
0.61
0.95
0.92
1.03
0.96
0.87
1.38
0.98
0.88
0.95
0.89
0.97
0.84-1.08
0.80-1.06
0.82-1.29
0.78-1.17
0.73-1.04
0.92-2.08
0.85-1.13
0.74-1.06
0.68-1.32
0.64-1.24
0.85-1.10
15q25, rs6495309,T cases controls p-value OR 95%CI
1.0 1.5 2.0Odds ratio (95% CI)
Men
Women
Never
Current
Former
Adenocarcinoma
Squamous carcinoma
Small Cell Lung Cancer
<=50
>50
Overall
By Gender (Phet=0.05)
By Smoking (Phet=0.81)
By Histology (Phet= 0.82)
By Age (Phet=0.61)
2,338
1,717
621
829
254
1,255
1,307
825
179
399
1,939
3,077
2,084
993
1,266
226
1,585
3,077
3,077
3,077
442
2,635
0.005
0.19
1.3*10-3
0.02
0.04
0.63
4.4*10-3
0.13
0.34
0.14
0.02
0.88
0.93
0.77
0.84
0.87
0.93
0.86
0.90
0.89
0.84
0.89
0.81-0.96
0.84-1.03
0.65-0.90
0.72-0.97
0.77-0.99
0.69-1.25
0.77-0.95
0.79-1.03
0.70-1.13
0.66-1.06
0.81-0.98
CLPTM1L, rs401681, T cases controls p-value OR 95%CI
0.7 0.8 0.9 1.0 1.2
Odds ratio (95% CI)
Men
Women
Never
Current
Former
Adenocarcinoma
Squamous carcinoma
Small Cell Lung Cancer
<=50
>50
Overall
By Gender (Phet=0.13)
By Smoking (Phet=0.38)
By Histology (Phet=0.07)
By Age (Phet=0.78)
2,338
1,717
621
829
254
1,255
1,307
825
179
399
1,939
3,077
2,084
993
1,266
226
1,585
3,077
3,077
3,077
442
2,635
2.1*10-7
4.1*10-4
5.3*10-5
5.7*10-6
8.1*10-4
0.26
4.8*10-9
0.05
0.30
0.03
1.7*10-6
1.30
1.23
1.46
1.47
1.28
1.22
1.41
1.15
1.15
1.35
1.29
1.17-1.43
1.10-1.38
1.21-1.75
1.24-1.74
1.11-1.48
0.87-1.70
1.26-1.59
1.00-1.34
0.88-1.49
1.04-1.75
1.16-1.44
TERT, rs2736100, C cases controls p-value OR 95%CI
1.0 1.2 1.4 1.6 1.8Odds ratio (95% CI)
Men
Women
Never
Current
Former
Adenocarcinoma
Squamous carcinoma
Small Cell Lung Cancer
<=50
>50
Overall (RSQR= 0.99)
By Gender (Phet=0.77)
By Smoking (Phet=0.10)
By Histology (Phet=0.22)
By Age (Phet=0.02)
2,338
1,717
621
829
254
1,255
1,307
825
179
399
1,939
3,077
2,084
993
1,266
226
1,585
3,077
3,077
3,077
442
2,635
0.03
0.06
0.20
0.54
0.01
0.44
0.19
0.03
0.46
0.17
2.8*10-3
1.10
1.11
1.07
0.95
1.18
1.14
1.07
1.16
0.91
0.84
1.16
1.01-1.20
1.00-1.23
0.91-1.27
0.82-1.11
1.04-1.34
0.84-1.53
0.97-1.19
1.02-1.32
0.72-1.16
0.66-1.08
1.05-1.27
9p21, rs1333040,C cases controls p-value OR 95%CI
0.8 1.0 1.2 1.4
Odds ratio (95% CI)
Odds ratio (95% CI)
Men
Women
Never
Former
Current
Adenocarcinoma
Squamous carcinoma
Small Cell Lung Cancer
<=50
>50
Overall
By Gender (Phet =0.72)
By Smoking (Phet =0.26)
By Histology (Phet =0.98)
By Age (Phet =0.14)
2,338
1,717
621
829
254
1,255
1,307
825
179
399
1,939
3,077
2,084
993
1,266
226
1,585
3,077
3,077
3,077
442
2,635
0.43
0.66
0.49
0.88
0.06
0.69
0.49
0.45
0.81
0.29
0.19
0.97
0.98
0.94
0.99
0.76
0.97
0.96
0.95
0.97
1.13
0.94
0.88-1.05
0.88-1.08
0.80-1.11
0.86-1.14
0.56-1.02
0.86-1.11
0.87-1.07
0.84-1.08
0.77-1.23
0.90-1.42
0.85-1.03
12p13, rs10849605,Tcases controls p-value OR 95%CI
0.6 0.8 1.0 1.2 1.4
Men
Women
Never
Former
Current
Adenocarcinoma
Squamous carcinoma
Small Cell Lung Cancer
<=50
>50
Overall
By Gender (Phet =0.54)
By Smoking (Phet =0.79)
By Histology (Phet =0.42)
By Age (Phet =0.88)
2,338
1,717
621
829
254
1,255
1,307
825
179
399
1,939
3,077
2,084
993
1,266
226
1,585
3,077
3,077
3,077
442
2,635
0.72
0.49
0.77
0.88
0.45
0.71
0.29
0.92
0.35
1.00
0.69
0.98
0.97
1.02
0.99
1.06
0.95
0.95
0.99
1.11
1.00
0.98
0.91-1.07
0.88-1.06
0.88-1.19
0.86-1.13
0.80-1.39
0.85-1.08
0.86-1.04
0.88-1.12
0.89-1.39
0.80-1.25
0.90-1.07
2q32.1, rs11683501, G1 cases controls p-value OR 95%CI
0.8 0.9 1.0 1.1 1.3
Odds ratio (95% CI)
Figure S5. Stratified Analysis of Association Between SNPs on 2q32 (A), 5p15 (B), 9p21 (C), 12p13 (D) and 15q25 (F) and the Risk of Lung Cancer in the Han Chinese population.Combined Odds Ratios (ORs) and 95%Confidence Intervals (CIs) were derived from the per-allele model. Squares represent odds ratios; size of the square represents inverse of the variance of the log odds ratio; horizontal lines represent 95% confidence intervals; diamonds represent summary estimate combining the study-specific estimates with a fixed-effects model; solid vertical lines represent an odds ratio of 1; dashed vertical lines represent the overall odds ratio. 1 For the 2q32 the most significant results were observed for the squamous cell carcinoma histology when adjusted by smoking status. Here the results for the model without additional adjustment for smoking is presented as results were similar between these two models (data not presented) in the Han Chinese population.
Figure S6. Regional plot 15q25 locus using imputed data in the Chinese Hap population.Results (-log10P) are shown for SNPs genotyped and imputed within the region. The most significant SNP in the locus are shown diamond-shaped and the r2 values for the rest of the SNPs are indicated by different colours depending on the LD level in CHB+JPT population. The genes within the region are annotated and shown as arrows. The known lung cancer variants rs16969968 (MAF=0.03, OR=0.37, P = 0.05) and rs1051730 (MAF=0.03, OR=0.34, P=0.05) were imputed in the Han Chinese with a low quality (RSQR<0.06) and did not pass the quality cut-off of RSQR > 0.30 to be included in the analysis.
(A) (B)
Figure S7. Stratified Analysis of Association Between SNPs on 2q32 (A) and 15q15.1 (B) and the Risk of Lung Cancer.Combined Odds Ratios (ORs) and 95%Confidence Intervals (CIs) were derived from the per-allele model. Results for fixed effect model are presented unless otherwise specified. Squares represent odds ratios; size of the square represents inverse of the variance of the log odds ratio; horizontal lines represent 95% confidence intervals; diamonds represent summary estimate combining the study-specific estimates with a fixed-effects model; solid vertical lines represent an odds ratio of 1; dashed vertical lines represent the overall odds ratio. For the 2q32 the most significant results were observed for the squamous cell carcinoma histology when adjusted by smoking status. Therefore results for the variant at chromosome 2 – rs11683501 are presented for the model adjusted by smoking for all subgroups except never, former, current and ever smokers where the models were not adjusted by smoking status. 1 Heterogeneity assessed between ever and never smoking groups.NSCLC – non small cell lung cancer
Random effects models
IARCSLRIMDACCdeCodeHGFICRLiverpoolNCIHarvard
MenWomen
NeverFormerCurrentEver
AdenocarcinomaSquamous carcinomaSmall Cell Lung CancerLarge Cell Lung cancer
Stage 1 and 2 Stage 3 and 4
yesno
<=50>50
Fixed effect model
By study (Phet = 0.10)
By Gender (Phet =0.56 )
By Smoking (Phet =0.16)1
By Histology (Phet =0.87)
By Stage NSCLC (Phet =0.64)
By Family History of Lung cancer (Phet =0.62 )
By Age (Phet =3.8*10-4)
1486014860
2865330
1149830487
1949542
5724984
86683701
92446648242
13793
479941001967
283
24103712
192410618
135011018
2938529385
4228499
113411207
480269824995670
970
148369354
91719608
1021222342
28389285342643016578
1097110971
754725011
506619122
1.2e-061.8e-04
0.430.58
0.0030.040.540.02
6e-040.030.61
0.0010.15
0.994.9e-05
0.022.9e-06
0.020.001
0.050.52
0.080.004
0.034.1e-05
0.044.8e-06
0.920.91
0.971.070.820.890.930.900.770.940.96
0.930.95
1.000.890.940.92
0.940.910.930.94
0.940.92
0.900.92
1.110.91
0.89-0.950.87-0.96
0.90-1.050.85-1.350.72-0.940.79-0.990.75-1.160.82-0.980.66-0.890.88-0.990.84-1.11
0.89-0.970.89-1.02
0.89-1.120.83-0.940.89-0.990.88-0.95
0.89-0.990.86-0.960.86-1.000.78-1.13
0.87-1.010.86-0.97
0.82-0.990.89-0.96
1.00-1.230.88-0.95
15q15, rs504417, G cases controls p-value OR 95%CI
0.7 0.9 1.1 1.3
Odds Ratios (95%CI)
Random effects models
IARCSLRIMDACCdeCodeHGFNCIHarvard
MenWomen
NeverFormerCurrentEver
AdenocarcinomaSquamous carcinomaSmall lung cancerLarge lung cancer
Stage 1 and 2 Stage 3 and 4
yesno
<=50>50
Fixed effect model
By study (Phet = 0.93)
By Gender (Phet =0.22 )
By Smoking (Phet =0.03)1
By Histology (Phet =3*10-4)
By Stage NSCLC (Phet =0.79)
By Family History of Lung cancer (Phet =0.84)
By Age (Phet=0.28 )
1224812248
276333111498294875705984
36782452
9244664825113801
232732561340113
23121339
7634261
122210925
2408324083
40834991134112274805690970
42368438
918996251021322376
17499232332112912197
82932603
180015157
490019059
0.170.17
0.180.430.730.750.720.360.70
0.090.92
0.090.590.010.02
0.631.6x10-7
0.740.55
0.480.41
0.450.18
0.520.12
1.031.03
1.050.921.021.020.951.031.03
1.061.00
0.911.021.061.04
0.981.171.011.09
1.031.04
1.061.04
0.961.03
0.99-1.060.99-1.06
0.98-1.140.74-1.140.91-1.150.92-1.130.74-1.230.97-1.080.90-1.17
0.99-1.140.92-1.07
0.82-1.010.96-1.071.01-1.111.01-1.08
0.92-1.051.10-1.240.93-1.100.82-1.45
0.96-1.100.95-1.15
0.91-1.220.98-1.10
0.85-1.090.99-1.07
2q32.1, rs11683501, G cases controls p-value OR 95%CI
0.8 1.0 1.2
Odds Ratios (95%CI)
Figure S8. Power to detect lung cancer susceptibility alleles in the overall meta-analysis (black) and squamous cell histology (red). Power to identify susceptibility alleles was calculated over different minor allele frequencies (MAF) and for various effect sizes: RR=1.20 (solid lines), RR=1.10 (dot lines) and RR=1.05 (dashed lines). Power to detect 5p15 (rs401681, rs2736100), 6p21(rs3117582 ), 15q25 (rs6495309, rs1051730), 9p21 (rs1333040), 12p13 (rs10849605 ) and 15q15 (rs504417) SNPs was calculated for overall sample size (black dots) and, additionally, power to detect 9p21 (rs1333040) and 12p13 (rs10849605 ) variants was calculated for squamous cell carcinoma histology only (red dots). Power calculation was performed for log-additive model of inheritance using QUANTO 1.2.4 (Gauderman et al., 2002) and stipulating significance of 5*10 -8.
0.0 0.1 0.2 0.3 0.4 0.5
MAF
Po
we
r
Overall analysis
RR=1.20
RR=1.10RR=1.05
5p15 5p156p21
9p21
12p13
15q25 15q25
15q15
0%
20%
40%
60%
80%
100%
