Background
Methods
Study cohorts
Variable definitions
Genotyping quality control and imputation
Statistical analysis
Results
GWAS of CB COPD relative to smokers with normal spirometry
COPDGene NHWs | GenKOLS | ECLIPSE | ||||
---|---|---|---|---|---|---|
COPD with CB | Controls | COPD with CB | Controls | COPD with CB | Controls | |
n | 844 | 2,534 | 311 | 808 | 507 | 178 |
Age, years | 62.8 (8.3) | 59.5 (8.7) | 65.3 (10.0) | 55.6 (9.7) | 62.3 (7.7) | 57.5 (9.4) |
Pack-years | 59.2 (28.6) | 37.8 (20.3) | 33.9 (20.2) | 19.7 (13.6) | 51.6 (30.2) | 32.1 (24.8) |
Current smoker (%) | 53.3 | 39.6 | 54.0 | 41.2 | 51.4 | 40.1 |
FEV1,% predicted | 48.6 (17.4) | 96.8 (11.0) | 46.9 (16.8) | 94.9 (9.2) | 46.3 (15.3) | 107.9 (13.7) |
Sex (% male) | 61.8 | 49.3 | 64.6 | 50.1 | 75.7 | 57.9 |
Locus | Nearest gene | SNP | Risk allele | FRQ | COPDGene NHWs | GenKOLS | ECLIPSE | Overall | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OR (95% CI) |
P
| OR (95% CI) |
P
| OR (95 CI) |
P
| OR (95% CI) |
P
|
I
2
|
Q
| |||||
4q22
|
FAM13A
| rs2869967 | C | 0.41 | 1.33 (1.17-1.51) | 9.92 × 10-6 | 1.56 (1.25-1.95) | 8.08 × 10-5 | 1.40 (1.04-1.88) | 2.66x10-2 | 1.38 (1.25-1.53) | 5.61 × 10-10 | 0 | 0.46 |
4q22
|
FAM13A
| rs2045517 | T | 0.40 | 1.33† (1.17-1.51) | 9.87 × 10-6 | 1.56† (1.25-1.95) | 7.88 × 10-5 | 1.40† (1.04-1.88) | 2.67 × 10-2 | 1.38 (1.25-1.53) | 5.63 × 10-10 | 0 | 0.46 |
4q22
|
FAM13A
| rs7671167 | T | 0.51 | 1.32 (1.16-1.49) | 1.69 × 10-5 | 1.44 (1.15-1.80) | 1.27 × 10-3 | 1.41 (1.06-1.87) | 1.73 × 10-2 | 1.35 (1.22-1.50) | 5.58 × 10-9 | 0 | 0.75 |
4q22
|
FAM13A
| rs2904259 | C | 0.50 | 1.31† (1.16-1.49) | 1.85 × 10-5 | 1.44† (1.15-1.80) | 1.33 × 10-3 | 1.41† (1.06-1.87) | 1.73 × 10-2 | 1.35 (1.22-1.49) | 6.25 × 10-9 | 0 | 0.75 |
11p15
|
EFCAB4A
| rs34391416 | A | 0.05 | 2.38 (1.81-3.13) | 6.11 × 10-10 | 1.21† (0.68-2.16) | 5.18 × 10-1 | 0.80† (0.35-1.79) | 5.79 × 10-1 | 1.93 (1.53-2.45) | 4.99 × 10-8 | 79 | 0.01 |
11p15
|
CHID1
| rs147862429 | T | 0.05 | 2.77† (2.02-3.81) | 2.90 × 10-10 | 1.34† (0.71-2.53) | 3.68 × 10-1 | 0.58† (0.24-1.39) | 2.23 × 10-1 | 2.09 (1.60-2.74) | 7.87 × 10-8 | 85 | 0.001 |
2q14
|
PCDP1
| rs139257032 | T | 0.02 | 2.78† (1.57-4.92) | 4.60 × 10-4 | 4.17† (1.82-9.57) | 7.41 × 10-4 | 10.79† (1.27-91.39 | 2.91 × 10-2 | 3.35 (2.12-5.30) | 2.53 × 10-7 | 0 | 0.4 |
15q26
|
MCTP2
| rs12910412 | G | 0.46 | 1.29† (1.14-1.46) | 4.37 × 10-5 | 1.30† (1.03-1.64) | 2.49 × 10-2 | 1.33† (0.98-1.78) | 6.37 × 10-2 | 1.30 (1.17-1.44) | 5.22 × 10-7 | 0 | 0.99 |
11p15
|
CHID1
| rs139090846 | T | 0.01 | 4.65† (2.77-7.80) | 5.67 × 10-9 | 1.13† (0.33-3.89) | 8.41 × 10-1 | 0.75† (0.19-2.91) | 6.78 × 10-1 | 3.15 (2.01-4.94) | 5.62 × 10-7 | 78 | 0.01 |
11p15
|
AP2A2
| rs143705409 | G | 0.05 | 2.62† (1.93-3.56) | 7.19 × 10-10 | 1.32† (0.73-2.40) | 3.61 × 10-1 | 0.52† (0.24-1.11) | 8.95 × 10-2 | 1.92 (1.49-2.49) | 6.16 × 10-7 | 88 | 0.0002 |
11p15
|
AP2A2
| rs185786041 | C | 0.05 | 2.61† (1.92-3.54) | 8.44 × 10-10 | 1.31† (0.73-2.35) | 4.26 × 10-1 | 0.54† (0.26-1.11) | 9.50 × 10-2 | 1.89 (1.47-2.44) | 9.20 × 10-7 | 88 | 0.0002 |
11p15
|
AP2A2
| rs117455145 | G | 0.05 | 2.61† (1.92-3.54) | 8.50 × 10-10 | 1.31† (0.73-2.34) | 4.27 × 10-1 | 0.54† (0.26-1.11) | 9.28 × 10-2 | 1.89 (1.46-2.43) | 9.68 × 10-7 | 88 | 0.0002 |
GWAS of CB COPD relative to COPD subjects without CB
COPDGene NHWs | GenKOLS | ECLIPSE | ||||
---|---|---|---|---|---|---|
CB | No CB | CB | No CB | CB | No CB | |
N | 844 | 1968 | 311 | 552 | 507 | 1257 |
Age, years | 62.8 (8.3) | 65.5 (8.0) | 65.3 (10.0) | 65.7 (10.1) | 62.3 (7.7) | 64.2 (6.8) |
Pack-years | 59.2 (28.6) | 55.1 (27.6) | 34.0 (20.4) | 30.9 (17.3) | 51.6 (30.2) | 49.8 (26.2) |
Current smoker (%) | 53.3 | 26.7 | 54.0 | 42.8 | 51.4 | 28.5 |
FEV1,% predicted | 48.6 (17.4) | 50.1 (18.2) | 46.9 (16.8) | 52.7 (17.5) | 46.3 (15.3) | 48.2 (15.7) |
Sex (% male) | 61.8 | 53.0 | 64.6 | 57.6 | 75.7 | 63.5 |
Locus | Nearest gene | SNP | Risk allele | FRQ | COPDGene NHWs | GenKOLS | ECLIPSE | Overall | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OR (95% CI) |
P
| OR (95% CI) |
P
| OR (95% CI) |
P
| OR (95% CI) |
P
|
I
2
|
Q
| |||||
1q23
|
RPL31P11
| rs114931935 | A | 0.04 | 1.98† (1.42-2.78) | 6.43 × 10-5 | 2.11† (1.07-4.15) | 3.10 × 10-2 | 1.64† (1.07-2.51) | 2.21 × 10-2 | 1.88 (1.47-2.40) | 4.99 × 10-7 | 0 | 0.74 |
1q23
|
RPL31P11
| rs114384494 | T | 0.04 | 2.01† (1.43-2.84) | 7.04 × 10-5 | 2.18† (1.08-4.38) | 2.92 × 10-2 | 1.61† (1.03-2.51) | 3.62 × 10-2 | 1.89 (1.47-2.44) | 8.86 × 10-7 | 0 | 0.67 |
1q23
|
ATF6
| rs924777 | G | 0.12 | 1.23† (1.03-1.46) | 2.20 × 10-2 | 1.21 (0.89-1.64) | 2.19 × 10-1 | 1.69 (1.36-2.10) | 2.30 × 10-6 | 1.36 (1.20-1.54) | 1.33 × 10-6 | 65 | 0.06 |
1q23
|
ATF6
| rs2298019 | A | 0.12 | 1.23† (1.03-1.47) | 1.98 × 10-2 | 1.25† (0.93-1.70) | 1.43 × 10-1 | 1.66† (1.33-2.06) | 6.41 × 10-6 | 1.36 (1.20-1.54) | 1.36 × 10-6 | 56 | 0.10 |
Complementary analyses
Locus | Gene | SNP | Risk allele | COPD with CBvs. smoking controls | COPD without CBvs. smoking controls | Permutation testing to assess difference of OR between two meta-analyses, 10,000 times | ||||
---|---|---|---|---|---|---|---|---|---|---|
FRQ | OR |
P
| FRQ | OR |
P
|
P
| ||||
4q22
|
FAM13A
| rs2869967* | C | 0.41 | 1.38 | 5.61 × 10-10 | 0.41 | 1.29 | 9.73 × 10-10 | 1.10 × 10-3 |
4q22
|
FAM13A
| rs4416442† | C | 0.40 | 1.38 | 6.87 × 10-10 | 0.41 | 1.29 | 6.97 × 10-10 | 2.30 × 10-3 |
4q22
|
FAM13A
| rs7671167† | T | 0.50 | 1.35 | 5.58 × 10-9 | 0.50 | 1.25 | 6.63 × 10-8 | 3.00 × 10-4 |
4q22
|
FAM13A
| rs1964516† | T | 0.50 | 1.35 | 1.04 × 10-8 | 0.50 | 1.24 | 1.12 × 10-7 | 8.00 × 10-4 |
4q31
|
HHIP-AS1
| rs13141641† | T | 0.58 | 1.27 | 2.81 × 10-6 | 0.59 | 1.25 | 2.18 × 10-8 | 1.77 × 10-1 |
4q31
|
HHIP-AS1
| rs13118928† | A | 0.58 | 1.24 | 2.72 × 10-5 | 0.59 | 1.25 | 3.15 × 10-8 | 4.54 × 10-1 |
15q25
|
CHRNA3
| rs12914385† | T | 0.42 | 1.27 | 2.83 × 10-6 | 0.42 | 1.22 | 7.86 × 10-7 | 5.75 × 10-2 |
15q25
|
AGPHD1
| rs8034191† | C | 0.37 | 1.27 | 4.29 × 10-6 | 0.37 | 1.22 | 1.34 × 10-6 | 5.13 × 10-2 |
15q25
|
IREB2
| rs11858836† | A | 0.35 | 1.25 | 4.10 × 10-5 | 0.36 | 1.23 | 9.27 × 10-7 | 4.19 × 10-1 |
19q13
|
RAB4B
| rs2604894† | G | 0.56 | 1.19 | 9.89 × 10-4 | 0.57 | 1.16 | 4.70 × 10-4 | 1.28 × 10-1 |
14q32
|
RIN3
| rs754388† | C | 0.81 | 1.22 | 3.74 × 10-3 | 0.82 | 1.29 | 2.37 × 10-6 | 5.84 × 10-2 |
14q32
|
RIN3
| rs17184313† | C | 0.82 | 1.20 | 6.85 × 10-3 | 0.83 | 1.28 | 4.36 × 10-6 | 1.92 × 10-2 |