Introduction
Material and methods
Study population
Polymorphisms and genotype data
Statistical analysis
Quality criteria
Main-effect analysis and confounder selection
Interaction analyses with logic regression
Results
Total | ABCFS | CECILE | ESTHER | GENICA | MARIE | MTLGEBCS | NBHS | OFBCR | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | |
N | 22,992 | 21,413 | 770 | 492 | 1,016 | 994 | 475 | 502 | 465 | 427 | 1,816 | 1,778 | 408 | 360 | 125 | 118 | 1,056 | 495 |
Reference age [years] (mean (SD)) | 56 (10) | 57 (9) | 40 (7) | 42 (9) | 54 (11) | 55 (11) | 61 (9) | 62 (7) | 57 (11) | 57 (12) | 62 (6) | 62 (6) | 62 (6) | 61 (6) | 53 (11) | 53 (11) | 53 (10) | 52 (9) |
Parity (n) | ||||||||||||||||||
Nulliparous 1+ full term pregnancies Unknown | 2,962 16,580 3,450 | 2,094 17,135 2,184 | 185 585 0 | 119 373 0 | 109 907 0 | 66 928 0 | 53 421 1 | 44 451 7 | 80 385 0 | 86 341 0 | 292 1,524 0 | 268 1,510 0 | 0 0 408 | 0 0 360 | 0 0 125 | 0 0 118 | 299 757 0 | 77 418 0 |
Ever breastfed (n) | ||||||||||||||||||
No Yes Unknown | 5,469 11,536 5,987 | 4,214 10,320 6,879 | 278 492 0 | 169 323 0 | 410 466 140 | 349 500 145 | 53 269 153 | 50 301 151 | 215 247 3 | 184 243 0 | 661 1,155 0 | 601 1,177 0 | 0 0 408 | 0 0 360 | 0 0 125 | 0 0 118 | 548 508 0 | 203 292 0 |
Family history of breast cancer (n) | ||||||||||||||||||
No Yes Unknown | 16,581 3,920 2,491 | 14,993 1,864 4,556 | 631 139 0 | 455 37 0 | 782 178 56 | 837 97 60 | 351 74 50 | 371 43 88 | 404 61 0 | 397 30 0 | 1,470 303 43 | 1,517 213 48 | 305 103 0 | 306 54 0 | 100 25 0 | 93 25 0 | 626 429 1 | 433 54 8 |
Ever smoking (n) | ||||||||||||||||||
No Yes Unknown | 6,279 6,601 10,112 | 8,202 7,408 5,803 | 348 421 1 | 235 257 0 | 617 399 0 | 601 393 0 | 297 175 3 | 325 166 11 | 270 195 0 | 225 202 0 | 989 827 0 | 950 827 1 | 0 0 408 | 0 0 360 | 0 0 125 | 0 0 118 | 424 479 153 | 239 256 0 |
Menopausal status (n) | ||||||||||||||||||
Pre-/peri-menopausal Post-menopausal Unknown | 5,851 12,933 4,208 | 5,526 12,167 3,720 | 534 139 97 | 220 129 143 | 375 577 64 | 341 593 60 | 50 412 13 | 25 454 23 | 128 331 6 | 118 304 5 | 221 1,595 0 | 176 1,602 0 | 0 0 408 | 0 0 360 | 10 26 89 | 17 23 78 | 189 714 153 | 217 278 0 |
Current use of estrogen-progesterone combined therapy (n) | ||||||||||||||||||
No Yes Unknown | 10,725 1,168 11,099 | 10,788 739 9,886 | 707 0 63 | 416 0 76 | 875 76 65 | 853 63 78 | 190 0 285 | 220 0 282 | 419 45 1 | 386 41 0 | 1,306 505 5 | 1,397 373 8 | 0 0 408 | 0 0 360 | 20 0 105 | 23 0 95 | 543 0 513 | 282 0 213 |
Tumor: ER status (n) | ||||||||||||||||||
Positive (ER+) Negative (ER−) Unknown | 14,724 3,516 4,752 | 447 254 69 | 805 141 70 | 302 98 75 | 336 119 10 | 1,347 400 69 | 353 53 2 | 0 125 0 | 595 250 211 | |||||||||
Tumor: PR status (n) | ||||||||||||||||||
Positive (PR+) Negative (PR−) Unknown | 10,016 4,768 8,208 | 500 201 69 | 665 271 80 | 260 135 80 | 313 142 10 | 1,141 605 70 | 303 102 3 | 0 125 0 | 504 322 230 |
PBCS | pKARMA | SASBAC | SBCS | SEARCH | SZBCS | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | |
N | 519 | 424 | 5,335 | 5,226 | 1,148 | 1,378 | 818 | 840 | 8,682 | 8,064 | 359 | 315 |
Reference age [years] (mean (SD)) | 56 (10) | 56 (10) | 58 (10) | 53 (10) | 63 (6) | 63 (6) | 59 (12) | 57 (6) | 54 (9) | 58 (9) | 56 (11) | 57 (10) |
Parity (n) | ||||||||||||
Nulliparous 1+ full term pregnancies Unknown | 85 434 0 | 42 382 0 | 817 4,470 48 | 196 4,553 477 | 164 984 0 | 133 1,245 0 | 123 695 0 | 99 741 0 | 755 5,418 2,509 | 964 6,193 907 | 0 0 359 | 0 0 315 |
Ever breastfed (n) | ||||||||||||
No Yes Unknown | 174 345 0 | 107 317 0 | 950 4,207 178 | 556 4,102 568 | 206 827 115 | 180 961 237 | 202 192 424 | 179 183 478 | 1,772 2,828 4,082 | 1,636 1,921 4,507 | 0 0 359 | 0 0 315 |
Family history of breast cancer (n) | ||||||||||||
No Yes Unknown | 473 46 0 | 395 29 0 | 4,189 979 167 | 4,196 560 470 | 0 176 972 | 0 116 1,262 | 701 117 0 | 758 82 0 | 6,363 1,251 1,068 | 5,218 524 2,322 | 186 39 134 | 17 0 298 |
Ever smoking (n) | ||||||||||||
No Yes Unknown | 222 297 0 | 203 220 1 | 2,186 3,095 54 | 2,401 2,816 9 | 650 498 0 | 793 585 0 | 182 109 527 | 440 400 0 | 36 29 8617 | 1,790 1,286 4,988 | 58 77 224 | 0 0 315 |
Menopausal status (n) | ||||||||||||
Pre-/peri-menopausal Post-menopausal unknown | 128 391 0 | 122 302 0 | 1,284 3,918 133 | 2,397 2,645 184 | 1 1,147 0 | 5 1,373 0 | 268 548 2 | 268 572 0 | 2,639 3,105 2,938 | 1,620 3,892 2,552 | 24 30 305 | 0 0 315 |
Current use of estrogen-progesterone combined therapy (n) | ||||||||||||
No Yes Unknown | 438 54 27 | 374 25 25 | 4,639 270 426 | 4,446 65 715 | 909 218 21 | 1,166 172 40 | 634 0 184 | 469 0 371 | 45 0 8,637 | 756 0 7,308 | 0 0 359 | 0 0 315 |
Tumor: ER status (n) | ||||||||||||
Positive (ER+) Negative (ER−) Unknown | 519 0 0 | 3,751 716 868 | 663 144 341 | 375 106 337 | 4,996 1,034 2,652 | 235 76 48 | ||||||
Tumor: PR status (n) | ||||||||||||
Positive (PR+) Negative (PR−) Unknown | 358 160 1 | 3,047 1,338 950 | 559 227 362 | 125 84 609 | 2,179 1,003 5,500 | 62 53 244 |
Main-effect analysis
SNP | Nearest gene | Chromosome, position (GRCh38.p13), and referent/variant alleles | ORa (95% CI) | p value ORa | ORb (95% CI) | p value ORb | BFDP for ORb Prior probability for effect (β ≠ 0) | ||
---|---|---|---|---|---|---|---|---|---|
0.1 | 0.05 | 0.01 | |||||||
dominant | |||||||||
rs7300641# | TPH2 | chr12:71,974,791: C:A | 1.046 (1.005–1.089) | 0.0290 | 1.071 (1.025–1.119) | 0.0023 | 0.3113 | 0.4883 | 0.8326 |
rs1386492# | TPH2 | chr12:71,968,485: A:G | 1.046 (1.005–1.089) | 0.0282 | 1.070 (1.024–1.118) | 0.0026 | 0.3393 | 0.5202 | 0.8496 |
rs1473473$ | TPH2 | chr12:72,010,598: A:G | 1.050 (1.009–1.094) | 0.0168 | 1.066 (1.020–1.114) | 0.0042 | 0.4562 | 0.6391 | 0.9022 |
rs4760751§ | TPH2 | chr12:71,984,138: G:A | 1.040 (0.997–1.084) | 0.0698 | 1.066 (1.018–1.116) | 0.0064 | 0.5240 | 0.6992 | 0.9237 |
rs1487276$ | TPH2 | chr12:72,011,279: G:A | 1.050 (1.008–1.093) | 0.0184 | 1.065 (1.019–1.113) | 0.0049 | 0.4855 | 0.6658 | 0.9121 |
rs1386489§ | TPH2 | chr12:71,955,510: A:G | 1.040 (0.998–1.085) | 0.0635 | 1.065 (1.017–1.115) | 0.0072 | 0.5509 | 0.7214 | 0.9310 |
rs1487281§ | TPH2 | chr12:71,986,242: A:C | 1.036 (0.994–1.081) | 0.0950 | 1.062 (1.014–1.112) | 0.0101 | 0.6267 | 0.7799 | 0.9486 |
rs7299582§ | TPH2 | chr12:71,962,534: A:G | 1.037 (0.994–1.081) | 0.0915 | 1.062 (1.014–1.112) | 0.0101 | 0.6267 | 0.7799 | 0.9486 |
rs17110627 | TPH2 | chr12:71,996,615: G:A | 0.967 (0.931–1.005) | 0.0844 | 0.958 (0.919–0.998) | 0.0412 | 0.8461 | 0.9207 | 0.9837 |
recessive | |||||||||
rs10857561 | MAPK8 | chr10:48,400,595: G:A | 1.118 (1.056–1.184) | 0.0001 | 1.106 (1.039–1.177) | 0.0016 | 0.2344 | 0.3926 | 0.7710 |
rs7075976 | MAPK8 | chr10:48,406,234: A:G | 1.064 (1.015–1.116) | 0.0097 | 1.064 (1.010–1.120) | 0.0193 | 0.7110 | 0.8385 | 0.9644 |
rs2129575 | TPH2 | chr12:71,946,293: C:A | 0.932 (0.859–1.012) | 0.0932 | 0.907 (0.830–0.991) | 0.0314 | 0.7572 | 0.8682 | 0.9717 |
rs17110627 | TPH2 | chr12:71,996,615: G:A | 0.940 (0.868–1.018) | 0.1268 | 0.905 (0.829–0.987) | 0.0235 | 0.7246 | 0.8475 | 0.9666 |
rs13515 | MAPK1 | chr22:21,761,597: G:A | 0.930 (0.840–1.031) | 0.1678 | 0.886 (0.792–0.991) | 0.0341 | 0.7713 | 0.8769 | 0.9738 |
Analysis by tumor hormone-receptor status
SNP | Nearest gene | Chromosome, position (GRCh38.p13), and referent/variant alleles | ORa (95% CI) | p value ORa | ORb (95% CI) | p value ORb | BFDP for ORb Prior probability for effect (β ≠ 0) | |||
---|---|---|---|---|---|---|---|---|---|---|
0.1 | 0.05 | 0.01 | ||||||||
ER+ | dominant | |||||||||
rs7300641 | TPH2 | chr12:71,974,791: C:A | 1.032 (0.986–1.081) | 0.1704 | 1.063 (1.012–1.117) | 0.0147 | 0.6935 | 0.8269 | 0.9614 | |
rs1386492 | TPH2 | chr12:71,968,485: A:G | 1.033 (0.987–1.081) | 0.1685 | 1.063 (1.011–1.117) | 0.0159 | 0.6934 | 0.8269 | 0.9614 | |
rs1473473 | TPH2 | chr12:72,010,598: A:G | 1.034 (0.987–1.082) | 0.1564 | 1.054 (1.003–1.107) | 0.0375 | 0.8156 | 0.9033 | 0.9799 | |
rs1487276 | TPH2 | chr12:72,011,279: G:A | 1.033 (0.987–1.081) | 0.1617 | 1.053 (1.002–1.106) | 0.0414 | 0.8268 | 0.9097 | 0.9813 | |
recessive | ||||||||||
rs7032571 | NFIL3 | chr9:91,428,391: A:G | 1.183 (1.043–1.342) | 0.0090 | 1.150 (1.003–1.317) | 0.0446 | 0.8021 | 0.8954 | 0.9781 | |
rs10857561 | MAPK8 | chr10:48,400,595: G:A | 1.107 (1.037–1.181) | 0.0021 | 1.097 (1.023–1.177) | 0.0095 | 0.5810 | 0.7453 | 0.9385 | |
rs1470747 | DDC | chr7:50,559,312: G:A | 0.917 (0.838–1.004) | 0.0602 | 0.902 (0.819–0.994) | 0.0373 | 0.7798 | 0.8820 | 0.9750 | |
PR+ | dominant | |||||||||
rs7300641 | TPH2 | chr12:71,974,791: C:A | 1.053 (1.000–1.110) | 0.0520 | 1.074 (1.016–1.134) | 0.0109 | 0.6005 | 0.7604 | 0.9430 | |
rs1386492 | TPH2 | chr12:71,968,485: A:G | 1.053 (1.000–1.110) | 0.0518 | 1.073 (1.016–1.133) | 0.0117 | 0.6205 | 0.7754 | 0.9473 | |
rs4760751 | TPH2 | chr12:71,984,138: G:A | 1.047 (0.991–1.106) | 0.0993 | 1.063 (1.004–1.126) | 0.0354 | 0.8070 | 0.8983 | 0.9787 | |
rs1386489 | TPH2 | chr12:71,955,510: A:G | 1.047 (0.992–1.106) | 0.0970 | 1.062 (1.003–1.125) | 0.0381 | 0.8167 | 0.9039 | 0.9800 | |
rs1473473 | TPH2 | chr12:72,010,598: A:G | 1.052 (0.998–1.108) | 0.0596 | 1.060 (1.002–1.120) | 0.0377 | 0.8126 | 0.9015 | 0.9795 | |
rs1487276 | TPH2 | chr12:72,011,279: G:A | 1.052 (0.998–1.108) | 0.0592 | 1.059 (1.003–1.119) | 0.0388 | 0.8225 | 0.9072 | 0.9808 | |
rs7299582 | TPH2 | chr12:71,962,534: A:G | 1.043 (0.988–1.102) | 0.1272 | 1.059 (1.001–1.122) | 0.0472 | 0.8424 | 0.9186 | 0.9833 | |
recessive | ||||||||||
rs7032571 | NFIL3 | chr9:91,428,391: A:G | 1.216 (1.054–1.402) | 0.0072 | 1.190 (1.025–1.381) | 0.0224 | 0.7467 | 0.8616 | 0.9701 | |
rs10857561 | MAPK8 | chr10:48,400,595: G:A | 1.090 (1.012–1.175) | 0.0238 | 1.092 (1.010–1.181) | 0.0276 | 0.7466 | 0.8615 | 0.9701 | |
ER− | dominant | |||||||||
rs1473473 | TPH2 | chr12:72,010,598: A:G | 1.109 (1.025–1.198) | 0.0095 | 1.124 (1.036–1.220) | 0.0051 | 0.4596 | 0.6423 | 0.9034 | |
rs1487276 | TPH2 | chr12:72,011,279: G:A | 1.109 (1.026–1.198) | 0.0095 | 1.124 (1.036–1.220) | 0.0052 | 0.4596 | 0.6423 | 0.9034 | |
rs4760751 | TPH2 | chr12:71,984,138: G:A | 1.075 (0.991–1.165) | 0.0823 | 1.099 (1.009–1.197) | 0.0294 | 0.7560 | 0.8674 | 0.9715 | |
rs1386489 | TPH2 | chr12:71,955,510: A:G | 1.071 (0.988–1.161) | 0.0975 | 1.095 (1.005–1.192) | 0.0375 | 0.7782 | 0.8810 | 0.9747 | |
rs7299582 | TPH2 | chr12:71,962,534: A:G | 1.067 (0.984–1.158) | 0.1159 | 1.091 (1.002–1.188) | 0.0460 | 0.8035 | 0.8962 | 0.9783 | |
rs17237290 | RORA | chr15:60,579,671: A:G | 0.880 (0.769–1.008) | 0.0643 | 0.845 (0.734–0.972) | 0.0187 | 0.6030 | 0.7623 | 0.9435 | |
rs16942767 | RORA | chr15:60,569,169: G:A | 0.873 (0.760–1.002) | 0.0533 | 0.831 (0.720–0.960) | 0.0121 | 0.6749 | 0.8142 | 0.9581 | |
rs16942772 | RORA | chr15:60,574,930: C:A | 0.869 (0.757–0.997) | 0.0459 | 0.829 (0.718–0.958) | 0.0109 | 0.6661 | 0.8081 | 0.9564 | |
recessive | ||||||||||
rs12229394 | TPH2 | chr12:71,999,134: G:A | 0.868 (0.747–1.008) | 0.0627 | 0.836 (0.715–0.978) | 0.0251 | 0.7660 | 0.8736 | 0.9730 | |
rs17110627 | TPH2 | chr12:71,996,615: G:A | 0.847 (0.718–0.998) | 0.0477 | 0.814 (0.685–0.967) | 0.0191 | 0.7547 | 0.8666 | 0.9713 | |
PR− | dominant | |||||||||
rs2289858 | MAP2K2 | chr19:4,102,625: A:G | 1.096 (0.999–1.203) | 0.0518 | 1.110 (1.009–1.221) | 0.0328 | 0.7610 | 0.8705 | 0.9722 | |
rs1473473 | TPH2 | chr12:72,010,598: A:G | 1.066 (0.995–1.142) | 0.0674 | 1.083 (1.008–1.162) | 0.0285 | 0.7454 | 0.8608 | 0.9699 | |
rs1487276 | TPH2 | chr12:72,011,279: G:A | 1.065 (0.994–1.141) | 0.0725 | 1.081 (1.007–1.160) | 0.0316 | 0.7648 | 0.8729 | 0.9728 | |
rs1549854 | MAP2K1 | chr15:66,404,397: C:A | 0.915 (0.851–0.985) | 0.0176 | 0.918 (0.851–0.990) | 0.0262 | 0.7413 | 0.8582 | 0.9693 | |
rs2289163 | RORA | chr15:60,590,769: A:C | 0.905 (0.812–1.010) | 0.0742 | 0.891 (0.796–0.997) | 0.0433 | 0.7982 | 0.8930 | 0.9775 | |
recessive | ||||||||||
rs8033552 | RORA | chr15:60,551,386: G:A | 1.195 (1.004–1.422) | 0.0452 | 1.250 (1.044–1.496) | 0.0151 | 0.7403 | 0.8575 | 0.9691 | |
rs10857561 | MAPK8 | chr10:48,400,595: G:A | 1.115 (1.011–1.229) | 0.0294 | 1.112 (1.005–1.229) | 0.0391 | 0.7802 | 0.8822 | 0.9750 | |
rs13515 | MAPK1 | chr22:21,761,597: G:A | 0.828 (0.687–0.997) | 0.0468 | 0.795 (0.656–0.964) | 0.0195 | 0.7741 | 0.8786 | 0.9742 |
Interaction analysis
Interaction/main effect† | Nearest Genes | ORa** (95% CI) | ORb** (95% CI) | BFDP for ORb Prior probability for effect (β ≠ 0) | ||
---|---|---|---|---|---|---|
0.1 | 0.05 | 0.01 | ||||
rs1386483R ∧ rs1473473D ∧ rs3729931D | TPH2, TPH2, RAF1 | 1.163 (1.064–1.270) | 1.201 (1.090–1.323) | 0.082 | 0.159 | 0.495 |
rs10857561R ∧ !rs1347069D | MAPK8, MAP2K1 | 1.156 (1.070–1.249) | 1.147 (1.053–1.248) | 0.247 | 0.409 | 0.783 |
rs1386483R ∧ rs1473473D ∧ !rs2269457D | TPH2, TPH2, NR1D1 | 1.095 (1.001–1.197) | 1.113 (1.009–1.227) | 0.759 | 0.869 | 0.972 |
rs10857561R | MAPK8 | 1.120 (1.056–1.188) | 1.109 (1.040–1.183) | 0.253 | 0.417 | 0.788 |
rs1386489D ∧ !rs3828057R | TPH2, RORC | 1.064 (1.015–1.114) | 1.084 (1.030–1.141) | 0.288 | 0.461 | 0.817 |
rs1473473D | TPH2 | 1.050 (1.007–1.094) | 1.067 (1.019–1.116) | 0.463 | 0.645 | 0.904 |
rs7075976R | MAPK8 | 1.068 (1.017–1.121) | 1.066 (1.010–1.124) | 0.710 | 0.838 | 0.964 |
rs7299582D | TPH2 | 1.038 (0.994–1.084) | 1.065 (1.015–1.116) | 0.580 | 0.745 | 0.938 |
!rs2171363R ∧ !rs7026487D ∧ !rs9610375R | TPH2, RORB, MAPK1 | 1.054 (1.010–1.101) | 1.051 (1.002–1.103) | 0.840 | 0.917 | 0.983 |
!rs12941497D | NR1D1 | 1.040 (1.000–1.081) | 1.044 (1.000–1.089) | 0.857 | 0.927 | 0.985 |