Nature Genetics: doi:10.1038/ng · Genetics, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;21...
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1 Supplementary Material A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4 by Beaty, Terri H, 1 Murray, Jeffrey C, 2 Marazita, Mary L, 3 Munger, Ronald G, 4 Ruczinski, Ingo, 1 Hetmanski, Jacqueline B, 1 Liang, Kung Yee, 1 Wu, Tao, 1,11 Murray, Tanda, 1 Fallin, M Daniele, 1 Redett, Richard A, 5 Raymond, Gerald, 5 Schwender, Holger, 1 Jin, Sheng- Chih, 1 Cooper, Margaret E, 3 Dunnwald, Martine, 2 Mansilla, Maria A, 2 Leslie, Elizabeth, 2 Bullard, Stephen, 6 Lidral, Andrew C, 6 Moreno, Lina M, 6 Menezes, Renato 3 , Vieira, Alexandre R 3 , Petrin, Aline, 2 Wilcox, Allen J, 7 Lie, Rolv T, 8 Jabs, Ethylin W, 9 Wu-Chou, Yah Huei, 10 Chen, Philip K, 10 Wang, Hong, 11 Ye, Xiaoqian, 9,12 Huang, Shangzhi, 13 Yeow, Vincent, 14 Chong, Samuel S, 15 Jee, Sun Ha, 16 Shi, Bing, 17 Christensen, Kaare 18 , Melbye, Mads 19 , Doheny, Kimberly F, 20 Pugh, Elizabeth W, 20 Ling, Hua 20 , Castilla, Eduardo E 21 , Czeizel, Andrew E, 22 Ma, Lian, 23 Field, L Leigh, 24 Brody, Lawrence C, 25 Pangilinan, Faith, 25 Mills, James L, 26 Molloy, Anne M, 27 Kirke, Peadar N, 28 Scott, John M, 27 Arcos- Burgos, Mauricio; 29 Scott, Alan F 5 Johns Hopkins University, School of Public Health, Baltimore, MD; 1 Department of Pediatrics, University of Iowa, Iowa City, IA; 2 University of Pittsburgh, School of Dental Medicine, Pittsburgh, PA; 3 Utah State University, Logan, UT; 4 Johns Hopkins University, School of Medicine, Baltimore, MD; 5 University of Iowa, Dept. of Orthodontics, Iowa City, IA; 6 NIEHS/NIH, Durham, North Carolina; 7 University of Bergen, Bergen, Norway; 8 Mt. Sinai Medical School, New York, NY; 9 Chang Gung Memorial Hospital, Taoyuan, Taiwan; 10 Peking University Health Science Center, Beijing, China; 11 Wuhan University, Wuhan, China; 12 Peking Union Medical College, Beijing, China; 13 KK Women’s & Children’s Hospital, Singapore; 14 National University of Singapore, Singapore; 15 Yonsei University, Epidemiology & Health Promotion, Seoul, Korea; 16 West China School of Stomatology, Sichuan University, Chengdu, China; 17 University of Southern Denmark, Odense, Denmark; 18 Statens Serum Institute, Copenhagen, Denmark; 19 Center for Inherited Disease Research, Johns Hopkins University, Baltimore MD; 20 Department of Genetics, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; 21 Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary; 22 School of Stomatology, Beijing University, Beijing, China, 23 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; 24 NHGRI/NIH, Bethesda MD, 25 NICHD/NIH, Bethesda, MD; 26 Trinity College Dublin, Dublin, Ireland, 27 Health Research Board, Dublin, Ireland; 28 University of Miami, Miller School of Medicine, Miami, FL 29 Nature Genetics: doi:10.1038/ng.580
Transcript of Nature Genetics: doi:10.1038/ng · Genetics, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;21...
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Supplementary Material
A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4
by
Beaty, Terri H,1 Murray, Jeffrey C,2 Marazita, Mary L,3 Munger, Ronald G,4 Ruczinski, Ingo,1 Hetmanski, Jacqueline B,1 Liang, Kung Yee,1 Wu, Tao,1,11 Murray, Tanda,1 Fallin, M Daniele,1 Redett, Richard A,5 Raymond, Gerald,5 Schwender, Holger,1 Jin, Sheng-Chih, 1 Cooper, Margaret E,3 Dunnwald, Martine,2 Mansilla, Maria A,2 Leslie, Elizabeth,2 Bullard, Stephen,6 Lidral, Andrew C,6 Moreno, Lina M,6 Menezes, Renato3, Vieira, Alexandre R3, Petrin, Aline,2 Wilcox, Allen J,7 Lie, Rolv T,8 Jabs, Ethylin W,9 Wu-Chou, Yah Huei,10 Chen, Philip K,10 Wang, Hong,11 Ye, Xiaoqian, 9,12 Huang, Shangzhi,13 Yeow, Vincent,14 Chong, Samuel S,15 Jee, Sun Ha,16 Shi, Bing,17 Christensen, Kaare18, Melbye, Mads19, Doheny, Kimberly F,20 Pugh, Elizabeth W,20 Ling, Hua20, Castilla, Eduardo E21, Czeizel, Andrew E,22 Ma, Lian,23 Field, L Leigh,24 Brody, Lawrence C,25 Pangilinan, Faith,25 Mills, James L,26 Molloy, Anne M,27 Kirke, Peadar N,28 Scott, John M,27 Arcos-Burgos, Mauricio;29 Scott, Alan F5 Johns Hopkins University, School of Public Health, Baltimore, MD;1 Department of Pediatrics, University of Iowa, Iowa City, IA;2 University of Pittsburgh, School of Dental Medicine, Pittsburgh, PA;3 Utah State University, Logan, UT;4 Johns Hopkins University, School of Medicine, Baltimore, MD;5 University of Iowa, Dept. of Orthodontics, Iowa City, IA;6 NIEHS/NIH, Durham, North Carolina;7 University of Bergen, Bergen, Norway;8 Mt. Sinai Medical School, New York, NY; 9 Chang Gung Memorial Hospital, Taoyuan, Taiwan;10 Peking University Health Science Center, Beijing, China;11 Wuhan University, Wuhan, China;12 Peking Union Medical College, Beijing, China;13 KK Women’s & Children’s Hospital, Singapore;14 National University of Singapore, Singapore;15 Yonsei University, Epidemiology & Health Promotion, Seoul, Korea;16 West China School of Stomatology, Sichuan University, Chengdu, China;17 University of Southern Denmark, Odense, Denmark;18 Statens Serum Institute, Copenhagen, Denmark;19 Center for Inherited Disease Research, Johns Hopkins University, Baltimore MD;20 Department of Genetics, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;21 Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary; 22 School of Stomatology, Beijing University, Beijing, China,23 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada;24 NHGRI/NIH, Bethesda MD, 25 NICHD/NIH, Bethesda, MD;26 Trinity College Dublin, Dublin, Ireland,27 Health Research Board, Dublin, Ireland;28 University of Miami, Miller School of Medicine, Miami, FL29
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Supplementary Note:
Samples: Case-parent trios used here originated from several research groups who
formed an international consortium to conduct a genome-wide search for genes
influencing risk to oral clefts using a case-parent trio design (supported by U01-DE-
018993). Cases with an isolated, non-syndromic oral cleft (CL; CLP; and CP) were
recruited over a period of years by different members of the consortium, typically
ascertained through a treatment center. Most cases were given a physical exam to
identify other congenital anomalies or developmental delays that could reflect a
recognized malformation syndrome. Parents were interviewed about family history of
clefts and other malformations, pregnancy history, parental medical histories, plus
maternal exposures to putative risk factors. DNA was collected from both the case and
his/her parents from a variety of biological specimens: whole blood (80.87%), buccal
brush/swab (11.17%), saliva (2.66%), mouthwash (1.83%) or dried blood spots (1.07%).
Each participating institution reviewed and approved research protocols for recruiting
human subjects, and US institutions reviewed and approved protocols of their foreign
collaborators. After this International Cleft Consortium was formed in 2007, each
individual IRB reviewed and approved monitored data sharing protocols administered
through dbGaP.
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Supplementary Table 1: Number of trios by recruitment site noting complete and incomplete trios (those with 1 parent missing). Recruitment Site CL Trios
Complete (Incomplete)
CLP Trios Complete (Incomplete)
Total Trios Complete (Incomplete)
Utah 68(16) 96(20) 164(36) Norway 106(4) 174(8) 280(12) Korea 19(0) 40(2) 59(2) Maryland 19(12) 71(42) 90(54) Pittsburgh 26(2) 70(28) 96(30) Singapore 15(1) 45(7) 60(8) Taiwan 42(4) 176(11) 218(15) Iowa 16(9) 29(11) 45(20) Denmark 6(15) 15(12) 21(27) Philippines 0(0) 94(4) 94(4) Hubei Prov. 39(3) 136(9) 175(12) Shandong Prov. 54(21) 129(70) 183(91) Sichuan Prov. 43(3) 63(3) 106(6) Total 453(90) 1138(227) 1591(317)
*total includes probands of indeterminate cleft type: 2 in Hubei Prov.; 3 in Shandong Prov.
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Supplementary Table 2: SNPs showing at or near genome wide levels of significance in recognized or potential candidate genes from TDT analysis in 1908 CL/P case-parent trios.
SNP Position OR(case) 95%CI Asymptotic p-value MA
overall MAF
Freq. Euro.
Freq. Asian
PAX7 on chr. 1 rs4920520 18802429 1.262 (1.124,1.417) 8.53E-05 A 0.312 0.491 0.142 rs4920522 18812967 0.774 (0.694,0.864) 4.90E-06 C 0.642 0.485 0.802 rs17352100 18824699 1.380 (1.215,1.567) 7.32E-07 T 0.240 0.397 0.090 rs766325 18829045 0.762 (0.681,0.853) 2.37E-06 G 0.644 0.465 0.823 rs6695765 18851907 0.783 (0.708,0.867) 2.57E-06 T 0.562 0.455 0.675 rs742071 18852461 1.449 (1.261,1.666) 1.84E-07 T 0.234 0.431 0.048 rs6659735 18856284 0.776 (0.694,0.868) 8.59E-06 G 0.656 0.485 0.816 rs4920338 18863380 1.277 (1.140,1.430) 2.47E-05 T 0.312 0.446 0.177 rs2236832 18872418 1.223 (1.103,1.355) 1.27E-04 C 0.395 0.485 0.301
VAX1 on chr. 10 rs7078160 118817550 1.342 (1.204,1.495) 1.07E-07 A 0.333 0.194 0.456 rs4752028 118824981 1.284 (1.151,1.434) 7.98E-06 C 0.285 0.195 0.361
NTN1 and LOC728685 on chr. 17 rs2872615 8855418 0.774 (0.696,0.861) 2.48E-06 C 0.369 0.237 0.482 rs9788972 8860355 1.398 (1.248,1.565) 7.05E-09 A 0.254 0.289 0.221 rs4791330 8861324 1.361 (1.217,1.522) 6.81E-08 C 0.307 0.324 0.292 rs1880646 8870570 0.795 (0.716,0.883) 1.90E-05 C 0.411 0.270 0.532 rs4791331 8872807 1.296 (1.158,1.451) 6.80E-06 T 0.318 0.459 0.190 rs8076457 8884654 1.345 (1.157,1.563) 1.14E-04 T 0.147 0.279 0.035 rs9915089 8893619 1.341 (1.194,1.507) 7.56E-07 T 0.240 0.300 0.183 rs8069536 8897010 1.644 (1.373,1.968) 6.04E-08 T 0.084 0.128 0.046 rs8081823 8906276 1.277 (1.153,1.415) 2.64E-06 A 0.384 0.323 0.436
*the target allele was defined as the minor allele (MA) among parents of European ancestry
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Supplementary Table 3. Source population for families used in replication study of 5 SNPs Source Population N
families Genotype individuals Family Type Total Affected
Asian China 159 833 231 63 trios and 96 extended families
Philippines 172 1361 446 Extended families So. Asian India 51 322 100 Extended families European USA 424 1282 476 352 trios and 72 extended
families Denmark 346 1347 351 Nuclear families Hungary 25 106 29 Extended families Spain 32 117 37 Nuclear families Turkey 29 88 33 27 consanguineous trios and
2 families Ireland 293 890 309 Nuclear families
South/ Central America
Argentina 71 236 72 31 trios and 40 extended families
Colombia 271 1089 410 188 trios and 83 extended families
Guatemala 92 444 97 30 trios and 62 extended families
GRAND TOTAL 1965 8115 2591
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Supplementary Table 4: P-values for replication of 5 SNPs showing genome wide significance in GWAS using independent study populations
Source Population
# Pedi-grees
MAFB ABCA4 rs987525 rs13041247 rs11696257 rs560426 rs481931
Asian ancestry
China 159 0.5716 0.0518 0.0274 0.0707 0.0723 Philippines 172 0.8751 0.1172 0.0130 0.0015 0.1803 Sub-Total 331 0.6964 0.0161 0.0009 0.0003 0.0290
So. Asian India 51 0.1172 0.0638 0.1675 0.8299 0.0382 European ancestry
USA 424 9.9*10-09 0.0631 0.0151 0.4571 0.3543 Denmark 346 8.0*10-05 0.0194 0.1397 0.0657 0.2261 Hungary 25 NA1 0.8759 0.8759 0.5688 0.6899 Spain 32 0.0060 0.5775 0.5775 0.6700 0.6374 Turkey 29 0.0045 0.3657 0.6394 1.0000 0.5127
Ireland 293 0.0002 0.0137 NG2 0.0190 0.5791 Sub-total 1,149 1.1*10-16 0.0002 0.02313 0.0058 0.4418
South/ Central America
Argentina 71 0.0214 0.4024 0.2087 0.1573 0.9377 Colombia 271 0.0024 0.4062 NG2 0.2871 NG2
Guatemala 92 0.8005 0.2401 0.3864 0.7127 0.1763 Sub-total 434 0.0013 0.3375 0.9344 0.4487 0.2378
Combined Total 1965 3.0*10-13 0.0001 0.0013 3.3*10-5 0.0487 Bold font indicates significant at 5% level; 1: Not available; 2: Not genotyped
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Supplementary Table 5: SNPs giving p<10-5 from TDT among CL/P trios Supplementary table 5a: All CL/P trios Chr SNP Gene Position (bp) A1 A2 T U Chi-sq p-value 1 rs4920520 PAX7 18802429 A G 646 512 15.51 8.2200E-05 1 rs4920522 PAX7 18812967 T C 731 566 20.99 4.6100E-06 1 rs17352100 PAX7 18824699 T C 563 408 24.74 6.5500E-07 1 rs766325 PAX7 18829045 A G 698 532 22.40 2.2100E-06 1 rs6695765 PAX7 18851907 C T 845 662 22.22 2.4300E-06 1 rs742071 PAX7 18852461 T G 484 334 27.51 1.5700E-07 1 rs6659735 PAX7 18856284 A G 706 548 19.91 8.1300E-06 1 rs4920338 PAX7 18863380 T C 678 531 17.87 2.3600E-05 1 rs4655165 UBXD3 20434976 G A 742 589 17.59 2.7400E-05 1 rs2744759 LOC343384 22452385 G T 722 882 15.96 6.4700E-05 1 rs2275035 ABCA4 94317748 A G 612 765 17.00 3.7400E-05 1 rs4147827 ABCA4 94320668 C G 431 316 17.70 2.5800E-05 1 rs560426 ABCA4 94326026 G A 885 618 47.43 5.7000E-12 1 rs4847196 ABCA4 94327041 A G 600 756 17.95 2.2700E-05 1 rs952499 ABCA4 94331013 T C 880 684 24.56 7.1900E-07 1 rs2297636 ABCA4 94341410 G A 806 634 20.54 5.8300E-06 1 rs481931 ABCA4 94342604 A C 604 805 28.67 8.5700E-08 1 rs570926 ABCA4 94342806 G A 652 850 26.10 3.2400E-07 1 rs1211213 ABCA4 94344008 C T 557 700 16.27 5.5000E-05 1 rs4147816 ABCA4 94347368 A G 604 807 29.21 6.5100E-08 1 rs4147812 ABCA4 94347631 G T 607 808 28.55 9.1200E-08 1 rs4147811 ABCA4 94347644 A G 601 807 30.14 4.0200E-08 1 rs3827712 ABCA4 94347759 C T 604 805 28.67 8.5700E-08 1 rs3789432 ABCA4 94347896 C T 601 798 27.74 1.3900E-07 1 rs10782976 ABCA4 94353713 G A 640 794 16.54 4.7700E-05 1 rs4147804 ABCA4 94354815 T C 633 803 20.13 7.2500E-06 1 rs4147803 ABCA4 94354881 G C 635 809 20.97 4.6700E-06 1 rs3789451 ABCA4 94358916 T C 668 841 19.83 8.4500E-06 1 rs3789452 ABCA4 94360089 A T 530 704 24.53 7.3000E-07 1 rs2151846 ABCA4 94360275 C A 656 860 27.45 1.6100E-07 1 rs11802196 ABCA4 94366631 C A 672 844 19.51 9.9800E-06 1 rs6686599 ABCA4 94369419 A G 628 803 21.40 3.7300E-06 1 rs12057415 ABCD3 94602357 T C 722 888 17.12 3.5200E-05 1 rs2391467 ABCD3 94623031 T C 714 884 18.09 2.1100E-05 1 rs6674604 ALG14 95290127 A C 521 391 18.53 1.6700E-05 1 rs12047510 C1orf110 161108826 C T 311 420 16.25 5.5400E-05 1 rs17015076 HSD11B1 207979216 T C 305 425 19.73 8.9400E-06 1 rs17015169 TRAF3IP3 208003537 T C 784 590 27.39 1.6600E-07 1 rs1044516 IRF6 208026237 A C 566 750 25.73 3.9300E-07 1 rs2073485 IRF6 208029417 A G 513 745 42.79 6.1100E-11 1 rs2013162 IRF6 208035307 A C 620 879 44.75 2.2400E-11 1 rs861020 IRF6 208043734 A G 686 479 36.78 1.3200E-09 1 rs10863790 IRF6 208054670 C A 312 538 60.09 9.0600E-15 1 rs126280 C1orf107 208086447 A G 712 512 32.68 1.0900E-08 1 rs6689839 C1orf107 208093649 G A 791 643 15.27 9.3000E-05 1 rs2064163 C1orf107 208115442 T G 537 736 31.11 2.4400E-08 1 rs12063989 C1orf107 208116516 C T 341 520 37.21 1.0600E-09 1 rs932347 C1orf107 208122253 T C 592 457 17.37 3.0700E-05 1 rs4844913 C1orf107 208134740 A G 676 863 22.72 1.8700E-06 1 rs9429830 SYT14 208177160 T C 679 867 22.86 1.7400E-06 1 rs11119388 SYT14 208241040 G A 372 550 34.36 4.5700E-09 1 rs227178 SYT14 208283569 A G 691 876 21.84 2.9600E-06 1 rs2485893 SYT14 208414778 A G 651 840 23.96 9.8500E-07 1 rs10779526 SYT14 208418819 T C 651 841 24.20 8.7000E-07 1 rs12094311 SYT14 208435759 G A 532 719 27.95 1.2400E-07 1 rs12060567 C1orf133 208437213 A G 536 717 26.15 3.1700E-07 2 rs10495585 LOC729285 11909579 C A 226 317 15.25 9.4200E-05 2 rs4497881 FAM49A 16570372 C A 617 764 15.65 7.6300E-05 2 rs4441471 FAM49A 16578889 A G 621 776 17.20 3.3700E-05 2 rs11900952 THADA 43367540 A G 528 675 17.96 2.2500E-05 2 rs7568834 DYSF 71659620 T C 518 652 15.35 8.9500E-05
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2 rs1375347 HS6ST1 128767379 T C 645 511 15.53 8.1100E-05 2 rs1715008 MGAT5 134533486 G A 809 656 15.98 6.4100E-05 2 rs3815854 SLC4A3 220376982 G A 660 821 17.50 2.8700E-05 3 rs4547687 GRM7 6191211 T C 639 786 15.16 9.8600E-05 3 rs10428174 FHIT 59789088 G A 331 234 16.65 4.4900E-05 3 rs7632427 EPHA3 89617067 C T 490 660 25.13 5.3600E-07 3 rs10511145 EPHA3 89680369 T G 527 683 20.11 7.3000E-06 3 rs668668 COL8A1 100919114 C T 591 733 15.23 9.5200E-05 3 rs792841 COL8A1 100953998 G T 583 754 21.87 2.9200E-06 3 rs792835 COL8A1 100958985 C T 658 844 23.03 1.5900E-06 3 rs704570 COL8A1 100959832 T C 513 674 21.84 2.9700E-06 3 rs704574 COL8A1 100966463 A G 660 847 23.20 1.4600E-06 3 rs1038294 COL8A1 100986418 T C 381 511 18.95 1.3500E-05 3 rs793494 COL8A1 100991458 T C 488 626 17.10 3.5600E-05 3 rs704582 FILIP1L 101054616 C T 388 512 17.08 3.5800E-05 3 rs813218 FILIP1L 101075286 A G 641 823 22.63 1.9700E-06 3 rs1384062 FILIP1L 101080618 G T 608 767 18.39 1.8000E-05 3 rs793440 FILIP1L 101125866 T C 495 635 17.35 3.1200E-05 3 rs13317017 FILIP1L 101148211 A C 490 636 18.93 1.3600E-05 3 rs4244713 FILIP1L 101162274 T G 485 628 18.37 1.8200E-05 3 rs4075038 FILIP1L 101162776 T C 381 505 17.35 3.1000E-05 3 rs766778 FILIP1L 101234170 C T 605 764 18.47 1.7300E-05 3 rs4682355 C3orf52 113290409 G A 566 442 15.25 9.4000E-05 3 rs16859207 C3orf52 113306969 G A 456 332 19.51 9.9900E-06 3 rs6445188 NAALADL2 176199877 C T 353 250 17.59 2.7400E-05 3 rs9823496 LOC442097 177152590 C A 824 653 19.80 8.6100E-06 3 rs7637064 RTP4 188641223 C T 580 728 16.75 4.2700E-05 3 rs17447439 TP63 191032117 G A 171 103 16.88 3.9900E-05 4 rs17802266 SPON2 1148991 A C 344 454 15.16 9.8600E-05 4 rs10517249 LOC642305 32017986 C T 457 585 15.72 7.3300E-05 4 rs12640320 SHROOM3 77750361 A C 754 604 16.57 4.6900E-05 4 rs7694491 PGDS 95509273 T C 803 653 15.45 8.4600E-05 4 rs6823909 GRIA2 158547155 T C 399 519 15.69 7.4800E-05 4 rs12643097 PALLD 170038527 G A 864 698 17.64 2.6700E-05 4 rs7663350 FAT 187798792 T C 553 692 15.52 8.1700E-05 5 rs297838 SLIT3 168554351 T C 406 527 15.69 7.4500E-05 5 rs744579 SLIT3 168558819 C T 391 512 16.21 5.6600E-05 5 rs307805 FLT4 180010093 G A 227 149 16.18 5.7600E-05 6 rs760788 C6orf105 11878691 A G 796 643 16.27 5.5000E-05 6 rs980899 POU3F2 98926521 G A 513 656 17.49 2.8800E-05 6 rs1507774 POU3F2 98930798 C T 504 643 16.84 4.0600E-05 7 rs4725033 LOC729852 7820533 C T 464 348 16.57 4.6900E-05 7 rs10259688 PON2 94894875 C T 625 491 16.09 6.0400E-05 7 rs2434357 DOCK4 111553748 G A 675 828 15.57 7.9300E-05 8 rs17645417 NRG1 32470875 C T 728 582 16.27 5.4900E-05 8 rs7845898 NKAIN3 64008504 T C 464 608 19.34 1.0900E-05 8 rs7013934 WDR21C 88859742 T C 290 198 17.34 3.1200E-05 8 rs7819401 WDR21C 88900831 G A 450 595 20.12 7.2800E-06 8 rs12543318 WDR21C 88937456 A C 657 852 25.20 5.1700E-07 8 rs7015145 hCG_1814486 129778467 A G 693 546 17.44 2.9600E-05 8 rs9297775 hCG_1814486 129805894 A C 684 535 18.21 1.9800E-05 8 rs6996786 hCG_1814486 129817168 T G 675 535 16.20 5.7000E-05 8 rs6983287 hCG_1814486 129906406 A T 580 453 15.61 7.7700E-05 8 rs2395855 hCG_1814486 129909921 T C 329 494 33.08 8.8400E-09 8 rs11989880 hCG_1814486 129942164 T C 637 490 19.17 1.1900E-05 8 rs4733532 hCG_1814486 129950481 G A 324 483 31.33 2.1800E-08 8 rs1850889 hCG_1814486 129959587 A G 288 465 41.61 1.1200E-10 8 rs1519850 hCG_1814486 129966003 G A 251 415 40.38 2.0900E-10 8 rs1519849 hCG_1814486 129966149 A G 323 485 32.48 1.2000E-08 8 rs1157136 hCG_1814486 129971092 C T 712 550 20.80 5.1100E-06 8 rs1519847 hCG_1814486 129984942 A G 670 430 52.36 4.6100E-13 8 rs1530300 hCG_1814486 129988640 C T 530 333 44.97 2.0000E-11 8 rs1519841 hCG_1814486 129988982 G A 668 440 46.92 7.4100E-12 8 rs12542837 hCG_1814486 129995843 C T 668 435 49.22 2.2900E-12 8 rs987525 hCG_1814486 130015336 A C 554 311 68.26 1.4300E-16
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8 rs12548036 hCG_1814486 130017064 T G 628 408 46.72 8.2000E-12 8 rs7017252 hCG_1814486 130020026 T C 560 367 40.18 2.3100E-10 8 rs12547241 hCG_1814486 130021691 A G 555 377 34.00 5.5200E-09 8 rs1470206 hCG_1814486 130046646 C T 661 452 39.25 3.7400E-10 8 rs882083 hCG_1814486 130051938 T C 616 393 49.29 2.2100E-12 8 rs11787407 hCG_1814486 130054622 G A 604 404 39.68 2.9900E-10 8 rs12546523 hCG_1814486 130055292 A G 607 409 38.59 5.2400E-10 8 rs748978 hCG_1814486 130072298 T C 316 211 20.92 4.7900E-06 8 rs10808576 hCG_1814486 130133153 G T 691 550 16.02 6.2700E-05 9 rs2382469 NFIB 14368712 A C 672 829 16.40 5.0700E-05 9 rs4132699 SEMA4D 91226247 C A 843 684 16.60 4.7200E-05 10 rs1475084 EGR2 64275740 A G 662 832 19.34 1.0900E-05 10 rs10822065 EGR2 64280938 G T 527 670 17.08 3.5800E-05 10 rs10509173 EGR2 64281895 G A 661 830 19.16 1.2100E-05 10 rs7078160 VAX1 118817550 A G 766 571 28.44 9.6600E-08 10 rs4752028 VAX1 118824981 C T 727 566 20.05 7.5600E-06 10 rs11200059 LOC729426 123405580 T C 845 689 15.86 6.8100E-05 11 rs10891527 NCAM1 112657000 T C 392 286 16.57 4.6800E-05 11 rs617320 TRIM29 119466904 A C 774 626 15.65 7.6400E-05 11 rs1030467 NFRKB 129249462 G A 322 438 17.71 2.5800E-05 11 rs1016364 NFRKB 129250082 C T 330 442 16.25 5.5600E-05 11 rs1784394 JAM3 133468426 C T 84 228 66.46 3.5700E-16 13 rs8001641 LOC729485 79590812 A G 646 500 18.60 1.6100E-05 13 rs17473024 CLYBL 99036194 C T 647 514 15.24 9.4900E-05 13 rs12427494 CLYBL 99115495 C T 584 451 17.09 3.5600E-05 13 rs12184508 CLYBL 99150799 C T 665 525 16.47 4.9400E-05 13 rs1334586 ZIC2 99433607 G A 841 680 17.04 3.6600E-05 13 rs13542 ZIC2 99436393 A G 534 689 19.64 9.3300E-06 16 rs1876950 LOC653737 9240226 C T 682 836 15.62 7.7300E-05 16 rs959228 LOC653737 9248597 G A 687 840 15.33 9.0300E-05 16 rs7190139 LOC653737 9263812 T G 834 682 15.24 9.4700E-05 16 rs4788213 FAM57B 29942025 C T 680 836 16.05 6.1600E-05 17 rs2872615 LOC728685 8855418 C T 599 774 22.31 2.3300E-06 17 rs9788972 LOC728685 8860355 A G 717 513 33.83 6.0000E-09 17 rs1880646 NTN1 8870570 C T 625 786 18.37 1.8200E-05 17 rs4791331 NTN1 8872807 T C 692 534 20.36 6.4100E-06 17 rs9915089 NTN1 8893619 T C 664 495 24.64 6.9000E-07 17 rs8069536 NTN1 8897010 T G 314 191 29.96 4.4100E-08 17 rs8081823 NTN1 8906276 A G 838 656 22.17 2.4900E-06 17 rs227731 C17orf67 52128237 C A 842 683 16.58 4.6700E-05 18 rs1616887 TTR 27414750 G A 860 679 21.29 3.9500E-06 18 rs723744 TTR 27426474 A C 785 614 20.90 4.8400E-06 18 rs1667254 TTR 27440126 T C 779 621 17.83 2.4100E-05 18 rs4799585 TTR 27444172 T C 754 591 19.75 8.8100E-06 18 rs2852945 SMAD2 43573552 G A 812 655 16.80 4.1500E-05 19 rs8110645 ARHGEF18 7410404 C T 653 804 15.65 7.6200E-05 19 rs6510337 RHPN2 38237541 C T 638 790 16.18 5.7600E-05 20 rs11700244 MACROD2 15643993 A C 255 354 16.09 6.0300E-05 20 rs6029228 MAFB 38688962 G T 665 870 27.38 1.6700E-07 20 rs6072081 MAFB 38694468 G A 645 883 37.07 1.1400E-09 20 rs6065259 MAFB 38695393 A G 625 859 36.90 1.2500E-09 20 rs6102074 MAFB 38701599 G T 859 664 24.97 5.8300E-07 20 rs17820943 MAFB 38701930 T C 620 877 44.12 3.0900E-11 20 rs13041247 MAFB 38702488 C T 620 881 45.38 1.6200E-11 20 rs11696257 MAFB 38704230 T C 621 881 45.01 1.9600E-11 20 rs11698025 MAFB 38707497 A G 460 609 20.77 5.1800E-06 20 rs6102085 MAFB 38715043 G A 890 668 31.63 1.8600E-08 20 rs6016404 MAFB 38716134 A C 826 658 19.02 1.2900E-05 20 rs2064278 PARD6B 48796589 T G 361 489 19.28 1.1300E-05 20 rs6122972 PARD6B 48808649 G A 308 428 19.57 9.7200E-06 22 rs5765956 ARHGAP8 43529323 C T 908 725 20.51 5.9400E-06
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Supplementary Table 5b: SNPs giving p<10-5 among CL/P trios of Asian ancestry Chr SNP Gene Position (bp) A1 A2 T U Chi-sq p-value
1 rs2451672 KIAA0754 39640095 C A 82 148 18.94 1.3500E-05 1 rs12031088 CITED4 41157023 G A 350 461 15.19 9.7100E-05 1 rs7530899 LOC729708 77011319 G A 162 96 16.88 3.9700E-05 1 rs560426 ABCA4 94326026 G A 477 323 29.64 5.1900E-08 1 rs952499 ABCA4 94331013 T C 497 381 15.33 9.0500E-05 1 rs4147803 ABCA4 94354881 G C 336 445 15.21 9.6100E-05 1 rs3789452 ABCA4 94360089 A T 272 379 17.59 2.7500E-05 1 rs2151846 ABCA4 94360275 C A 367 501 20.69 5.4100E-06 1 rs6674604 ALG14 95290127 A C 263 171 19.50 1.0100E-05 1 rs12755096 ALG14 95309303 G A 261 171 18.75 1.4900E-05 1 rs4951357 ATP2B4 201911251 G A 312 435 20.25 6.7900E-06 1 rs17015169 TRAF3IP3 208003537 T C 480 353 19.36 1.0800E-05 1 rs1044516 IRF6 208026237 A C 376 538 28.71 8.3900E-08 1 rs2073485 IRF6 208029417 A G 322 530 50.78 1.0300E-12 1 rs2013162 IRF6 208035307 A C 337 552 52.00 5.5600E-13 1 rs861020 IRF6 208043734 A G 398 262 28.02 1.2000E-07 1 rs10863790 IRF6 208054670 C A 296 500 52.28 4.8100E-13 1 rs126280 C1orf107 208086447 A G 403 275 24.17 8.8400E-07 1 rs2064163 C1orf107 208115442 T G 326 516 42.87 5.8400E-11 1 rs12063989 C1orf107 208116516 C T 320 484 33.45 7.3000E-09 1 rs10863794 C1orf107 208130811 T C 415 305 16.81 4.1400E-05 1 rs4844913 C1orf107 208134740 G A 518 359 28.83 7.9200E-08 1 rs9429830 SYT14 208177160 C T 517 363 26.95 2.0900E-07 1 rs11119388 SYT14 208241040 G A 351 514 30.72 2.9900E-08 1 rs227178 SYT14 208283569 G A 530 377 25.81 3.7700E-07 1 rs2485893 SYT14 208414778 G A 523 375 24.39 7.8600E-07 1 rs10779526 SYT14 208418819 C T 524 375 24.70 6.7200E-07 1 rs12094311 SYT14 208435759 G A 379 516 20.97 4.6600E-06 1 rs12060567 C1orf133 208437213 A G 385 515 18.78 1.4700E-05 1 rs6604575 SPATA17 216249077 T C 0 33 33.00 9.2200E-09 1 rs4920176 SLC35F3 232519669 G A 210 136 15.83 6.9400E-05 2 rs8179791 HS6ST1 128773387 T C 353 256 15.45 8.4700E-05 2 rs840887 HS6ST1 128775685 T C 354 257 15.40 8.7000E-05 2 rs12992033 CENTG2 236270521 A G 305 410 15.42 8.6100E-05 2 rs1881191 CENTG2 236272663 T C 389 285 16.05 6.1800E-05 3 rs704570 COL8A1 100959832 T C 232 325 15.53 8.1300E-05 3 rs4682355 C3orf52 113290409 G A 374 272 16.11 5.9900E-05 3 rs16859207 C3orf52 113306969 G A 301 200 20.36 6.4100E-06 3 rs377374 STXBP5L 122061407 C A 409 305 15.15 9.9400E-05 3 rs390950 STXBP5L 122066323 A G 348 244 18.27 1.9200E-05 3 rs7647703 LOC730168 177869839 T C 75 34 15.42 8.6000E-05 3 rs711993 C3orf21 196161289 C T 475 342 21.65 3.2700E-06 3 rs860309 C3orf21 196178330 T C 365 481 15.91 6.6600E-05 4 rs12640320 SHROOM3 77750361 A C 481 363 16.50 4.8700E-05 4 rs12506428 GRID2 94049907 T C 364 510 24.39 7.8700E-07 4 rs977955 GRID2 94185503 A G 373 510 21.26 4.0200E-06 4 rs13140903 LOC645841 126781375 G A 488 360 19.32 1.1100E-05 4 rs17010239 LOC645841 126819148 C T 480 364 15.94 6.5300E-05 4 rs17028407 PET112L 153163883 A C 150 230 16.84 4.0600E-05 4 rs7663350 FAT 187798792 C T 490 362 19.23 1.1600E-05 5 rs32100 CTNND2 11333739 T C 465 336 20.78 5.1700E-06 5 rs258634 CTNND2 11338548 C A 469 351 16.98 3.7800E-05 5 rs763497 LOC728711 121455129 G A 179 263 15.96 6.4600E-05 6 rs11964049 BMP6 7654051 T G 370 268 16.31 5.3900E-05 6 rs12198986 BMP6 7665058 A G 377 271 17.34 3.1300E-05 6 rs2560776 LOC442162 13627351 T C 362 258 17.45 2.9600E-05 6 rs4712392 KRT18P38 19470037 G A 338 448 15.39 8.7300E-05 6 rs1580731 KRT18P38 19481304 A G 335 446 15.78 7.1300E-05 6 rs9366290 KRT18P38 19483118 A G 335 445 15.51 8.2000E-05 6 rs9380148 HCG9 30060684 A G 9 41 20.48 6.0300E-06 6 rs6906128 NOTCH4 32314282 C A 307 419 17.28 3.2300E-05
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7 rs6943366 LOC729852 7810246 T G 247 343 15.62 7.7400E-05 7 rs6969660 LOC729852 7812951 A C 379 509 19.03 1.2900E-05 7 rs7801961 LOC729852 7813445 G A 348 250 16.06 6.1400E-05 7 rs4725033 LOC729852 7820533 C T 344 243 17.38 3.0600E-05 7 rs2396301 IMMP2L 110454061 A G 459 348 15.27 9.3300E-05 7 rs6969349 FAM62B 158256804 A G 141 217 16.13 5.9000E-05 8 rs6998793 GPR124 37816032 C T 460 343 17.05 3.6500E-05 8 rs7845898 NKAIN3 64008504 T C 334 443 15.29 9.2200E-05 8 rs7819401 WDR21C 88900831 G A 296 407 17.53 2.8300E-05 8 rs976980 EXT1 118763820 A C 486 363 17.82 2.4300E-05 8 rs2656117 HAS2 122328463 T C 492 375 15.79 7.0800E-05 9 rs10491858 DMRT2 1500495 C T 146 86 15.52 8.1800E-05 9 rs7019932 DMRT2 1501184 T C 145 84 16.25 5.5500E-05 9 rs10810331 DMRT2 1502390 T C 147 83 17.81 2.4400E-05 9 rs10961846 DMRT2 1502748 T C 146 85 16.11 5.9800E-05 9 rs10810333 DMRT2 1502936 G A 146 86 15.52 8.1800E-05 9 rs7861233 TNC 116794937 C T 491 376 15.25 9.4000E-05 9 rs12341407 NR6A1 126360025 T C 401 294 16.47 4.9300E-05 9 rs7037310 NR6A1 126378897 T G 400 297 15.22 9.5600E-05
10 rs2224369 LOC219752 37893208 T C 500 381 16.07 6.0900E-05 10 rs7078160 VAX1 118817550 A G 506 380 17.92 2.3100E-05 11 rs288462 DCDC5 31004673 G A 336 445 15.21 9.6100E-05 11 rs566302 DCDC5 31047808 T C 336 447 15.74 7.2800E-05 11 rs565398 FAT3 91858879 A G 426 312 17.61 2.7100E-05 11 rs11608143 TMEM45B 129198876 T C 144 219 15.50 8.2700E-05 11 rs1030467 NFRKB 129249462 G A 155 235 16.41 5.1000E-05 11 rs1016364 NFRKB 129250082 C T 155 235 16.41 5.1000E-05 12 rs1402318 NAV3 76753767 G A 416 309 15.79 7.0700E-05 13 rs4942193 ENOX1 42668831 C T 151 230 16.38 5.1800E-05 15 rs2138831 VPS39 40280344 A G 147 224 15.98 6.4000E-05 15 rs7180279 GANC 40430830 G A 146 221 15.33 9.0400E-05 15 rs4924674 CAPN3 40455790 C T 149 228 16.55 4.7300E-05 15 rs12440452 ANXA2 58474522 A C 293 206 15.17 9.8300E-05 15 rs1869485 NARG2 58533897 G A 298 210 15.24 9.4500E-05 16 rs2019249 LOC440337 6391866 A G 520 400 15.65 7.6100E-05 16 rs2795534 LOC440337 6396058 A C 523 397 17.26 3.2700E-05 16 rs1003677 LOC440337 6396764 T C 385 277 17.62 2.7000E-05 16 rs2534735 LOC440337 6400998 G A 532 404 17.50 2.8700E-05 17 rs9788972 LOC728685 8860355 A G 380 263 21.29 3.9500E-06 17 rs4791330 LOC728685 8861324 C T 442 317 20.59 5.7000E-06 17 rs4791331 NTN1 8872807 T C 344 236 20.11 7.3100E-06 17 rs9915089 NTN1 8893619 T C 346 220 28.05 1.1800E-07 17 rs11651653 C17orf76 16364606 G A 221 145 15.78 7.1100E-05 17 rs6501633 SDK2 68926727 C T 358 261 15.20 9.6700E-05 17 rs8072292 SDK2 68926754 T C 358 260 15.54 8.0800E-05 17 rs8071926 MGAT5B 72475855 T C 369 483 15.25 9.4000E-05 18 rs16978256 SETBP1 40873147 A G 27 70 19.06 1.2700E-05 18 rs16978257 SETBP1 40875429 T G 28 69 17.33 3.1400E-05 19 rs10403459 IRGC 48905220 C T 289 404 19.08 1.2500E-05 20 rs6124225 MAFB 38326800 G A 354 257 15.40 8.7000E-05 20 rs6029228 MAFB 38688962 G T 360 497 21.90 2.8700E-06 20 rs6072081 MAFB 38694468 G A 343 499 28.90 7.6100E-08 20 rs6065259 MAFB 38695393 A G 338 485 26.26 2.9900E-07 20 rs6102074 MAFB 38701599 G T 485 355 20.12 7.2800E-06 20 rs17820943 MAFB 38701930 T C 338 506 33.44 7.3500E-09 20 rs13041247 MAFB 38702488 C T 337 507 34.24 4.8700E-09 20 rs11696257 MAFB 38704230 T C 338 508 34.16 5.0700E-09 20 rs11698025 MAFB 38707497 A G 319 458 24.87 6.1500E-07 20 rs735031 MAFB 38711056 T C 374 490 15.57 7.9300E-05 20 rs6102085 MAFB 38715043 A G 365 536 32.45 1.2200E-08 20 rs6016404 MAFB 38716134 A C 475 361 15.55 8.0600E-05 21 rs2834278 ITSN1 34141871 C T 488 372 15.65 7.6400E-05 22 rs3026685 PICK1 36792626 T C 480 364 15.94 6.5300E-05 22 rs139012 SCUBE1 41953916 G A 476 363 15.22 9.5700E-05
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Supplementary Table 5c: SNPs giving p<10-5 among CL/P trios of European ancestry Chr SNP Gene Position (bp) A1 A2 T U Chi-sq p-value 1 rs4920520 PAX7 18802429 A G 405 301 15.32 9.0800E-05 1 rs4920522 PAX7 18812967 C T 290 413 21.52 3.5000E-06 1 rs17352100 PAX7 18824699 T C 387 275 18.95 1.3400E-05 1 rs766325 PAX7 18829045 G A 289 399 17.59 2.7400E-05 1 rs6695765 PAX7 18851907 T C 283 399 19.73 8.9200E-06 1 rs742071 PAX7 18852461 T G 378 263 20.63 5.5700E-06 1 rs6659735 PAX7 18856284 G A 292 410 19.83 8.4400E-06 1 rs4920338 PAX7 18863380 T C 384 281 15.95 6.4900E-05 1 rs9426379 LOC391025 29721737 T C 199 127 15.90 6.6700E-05 1 rs9426282 LOC391025 29724323 A G 199 128 15.42 8.6300E-05 1 rs17305218 LOC645030 61471412 C T 51 100 15.90 6.6800E-05 1 rs4658367 ZNF326 90479854 G A 280 381 15.43 8.5500E-05 1 rs4420070 ZNF326 90481133 T C 280 381 15.43 8.5500E-05 1 rs428815 TGFBR3 92033508 T C 74 130 15.37 8.8300E-05 1 rs560426 ABCA4 94326026 G A 396 284 18.45 1.7500E-05 1 rs481931 ABCA4 94342604 A C 254 354 16.45 5.0000E-05 1 rs570926 ABCA4 94342806 G A 256 357 16.64 4.5200E-05 1 rs4147816 ABCA4 94347368 A G 252 354 17.17 3.4200E-05 1 rs4147812 ABCA4 94347631 G T 253 354 16.81 4.1400E-05 1 rs4147811 ABCA4 94347644 A G 250 354 17.91 2.3200E-05 1 rs3827712 ABCA4 94347759 C T 252 354 17.17 3.4200E-05 1 rs3789432 ABCA4 94347896 C T 250 346 15.46 8.4100E-05 1 rs3789688 ARHGAP29 94463828 A G 282 383 15.34 8.9800E-05 1 rs12057415 ABCD3 94602357 T C 291 411 20.51 5.9200E-06 1 rs2391467 ABCD3 94623031 T C 291 411 20.51 5.9200E-06 1 rs34347074 SLC16A1 113249328 A G 4 31 20.83 5.0200E-06 1 rs17015076 HSD11B1 207979216 T C 11 39 15.68 7.5000E-05 1 rs12747405 LOC643536 213689575 A G 2 27 21.55 3.4400E-06 2 rs13396069 LOC728597 3816101 C T 224 325 18.58 1.6300E-05 2 rs1607453 LOC442006 4195706 A G 3 27 19.20 1.1800E-05 2 rs798365 FAM49A 16760237 G A 149 225 15.44 8.5000E-05 2 rs11538422 PDK1 173171229 A C 6 35 20.51 5.9300E-06 2 rs3791498 HDAC4 239739972 A G 254 350 15.26 9.3800E-05 2 rs2290089 HDAC4 239750732 A C 252 352 16.56 4.7200E-05 2 rs3791523 HDAC4 239753412 A G 167 252 17.24 3.2900E-05 2 rs3791539 HDAC4 239767264 T C 184 273 17.33 3.1400E-05 2 rs3791549 HDAC4 239773961 A G 175 258 15.91 6.6400E-05 3 rs34233937 PRRT3 9964107 T C 6 39 24.20 8.6800E-07 3 rs9647406 KRT8P18 34910476 G A 186 116 16.23 5.6200E-05 3 rs10514688 KRT8P18 34937673 C T 186 115 16.75 4.2700E-05 3 rs771571 NFKBIZ 103139117 G C 276 378 15.91 6.6500E-05 3 rs13084588 BBX 108891794 G A 210 129 19.35 1.0900E-05 3 rs12495611 LOC730030 152014291 T G 117 185 15.31 9.1200E-05 4 rs10018486 D4S234E 4414543 G A 272 382 18.50 1.7000E-05 4 rs17001970 SHROOM3 77589062 T C 43 88 15.46 8.4400E-05 4 rs11737434 UNC5C 96341638 T C 272 378 17.29 3.2200E-05 4 rs3775003 UNC5C 96390234 A G 372 264 18.34 1.8500E-05 4 rs4254782 UNC5C 96400057 G A 278 394 20.02 7.6500E-06 4 rs28710412 TACR3 104977731 A G 2 23 17.64 2.6700E-05 4 rs4361343 LOC729971 164036804 A G 354 257 15.40 8.7000E-05 5 rs10056116 LOC442128 1729638 A G 320 228 15.45 8.4900E-05 5 rs10051014 LOC442128 1729668 C T 319 228 15.14 9.9900E-05 6 rs760788 C6orf105 11878691 G A 275 376 15.67 7.5400E-05 6 rs760787 C6orf105 11878763 T C 262 369 18.14 2.0500E-05 6 rs28470596 MICB 31566612 T C 32 89 26.85 2.2000E-07 6 rs6905353 MLN 33921021 G T 231 324 15.58 7.8900E-05 6 rs4946263 DCBLD1 117963452 C T 283 195 16.20 5.7000E-05 6 rs751873 SYNJ2 158410767 T C 271 378 17.64 2.6700E-05 7 rs11977445 SDK1 3982056 T G 13 44 16.86 4.0300E-05 8 rs1866994 IMPAD1 58152646 C A 177 270 19.35 1.0900E-05 8 rs12543318 WDR21C 88937456 C A 370 265 17.36 3.0900E-05
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8 rs7015145 hCG_1814486 129778467 A G 408 296 17.82 2.4300E-05 8 rs9297775 hCG_1814486 129805894 A C 401 288 18.53 1.6700E-05 8 rs1030608 hCG_1814486 129808934 A G 406 293 18.27 1.9200E-05 8 rs1030609 hCG_1814486 129809059 A C 398 290 16.95 3.8300E-05 8 rs6996786 hCG_1814486 129817168 T G 395 289 16.43 5.0600E-05 8 rs6983287 hCG_1814486 129906406 A T 367 233 29.93 4.4900E-08 8 rs2395855 hCG_1814486 129909921 T C 222 381 41.93 9.4800E-11 8 rs4733653 hCG_1814486 129913853 C T 261 401 29.61 5.2900E-08 8 rs11989880 hCG_1814486 129942164 T C 415 270 30.69 3.0200E-08 8 rs4733532 hCG_1814486 129950481 G A 227 376 36.82 1.3000E-09 8 rs1850889 hCG_1814486 129959587 A G 220 380 42.67 6.4900E-11 8 rs1519850 hCG_1814486 129966003 G A 189 341 43.59 4.0400E-11 8 rs1519849 hCG_1814486 129966149 A G 226 379 38.69 4.9600E-10 8 rs1157136 hCG_1814486 129971092 T C 277 430 33.11 8.7100E-09 8 rs1519847 hCG_1814486 129984942 A G 439 256 48.19 3.8800E-12 8 rs1530300 hCG_1814486 129988640 C T 432 250 48.57 3.1900E-12 8 rs1519841 hCG_1814486 129988982 G A 436 259 45.08 1.8900E-11 8 rs12542837 hCG_1814486 129995843 C T 439 255 48.78 2.8600E-12 8 rs987525 hCG_1814486 130015336 A C 390 194 65.78 5.0400E-16 8 rs12548036 hCG_1814486 130017064 T G 433 260 43.19 4.9700E-11 8 rs7017252 hCG_1814486 130020026 T C 427 280 30.56 3.2300E-08 8 rs12547241 hCG_1814486 130021691 G A 283 417 25.65 4.0900E-07 8 rs1470206 hCG_1814486 130046646 T C 285 419 25.51 4.4100E-07 8 rs882083 hCG_1814486 130051938 T C 441 277 37.46 9.3300E-10 8 rs11787407 hCG_1814486 130054622 A G 280 432 32.45 1.2200E-08 8 rs12546523 hCG_1814486 130055292 G A 280 430 31.69 1.8100E-08 8 rs748978 hCG_1814486 130072298 T C 179 87 31.82 1.6900E-08 8 rs2197111 hCG_1814486 130084897 T C 192 119 17.14 3.4800E-05 8 rs7018275 hCG_1814486 130085681 C T 192 119 17.14 3.4800E-05 8 rs1372452 hCG_1814486 130098216 A G 199 119 20.13 7.2500E-06 8 rs12334809 hCG_1814486 130100188 T C 201 120 20.44 6.1600E-06 8 rs11996876 hCG_1814486 130156354 C T 231 152 16.30 5.4200E-05 9 rs16908770 ELAVL2 24717103 G A 92 42 18.66 1.5700E-05 9 rs16908797 ELAVL2 24723492 T G 82 38 16.13 5.9000E-05 9 rs1475537 GADD45G 91402570 T C 305 216 15.20 9.6500E-05 9 rs3138512 GADD45G 91412273 A G 268 180 17.29 3.2200E-05 9 rs2329385 GADD45G 91466675 A C 284 386 15.53 8.1300E-05 9 rs4876993 GADD45G 91471223 T C 398 295 15.31 9.1300E-05 10 rs11817394 LOC642384 1525202 T C 145 80 18.78 1.4700E-05 10 rs12243246 LOC642384 1536496 T C 145 80 18.78 1.4700E-05 10 rs2676774 LOC642384 1543772 A G 147 82 18.45 1.7400E-05 10 rs7073086 LOC439954 36570372 A G 197 289 17.42 3.0000E-05 10 rs1451185 LOC439954 36600414 C T 194 281 15.93 6.5600E-05 10 rs2598576 LOC439954 36603489 A G 183 271 17.06 3.6300E-05 10 rs1475084 EGR2 64275740 G A 384 281 15.95 6.4900E-05 10 rs10822065 EGR2 64280938 G T 279 386 17.22 3.3400E-05 10 rs10509173 EGR2 64281895 A G 383 279 16.34 5.3000E-05 10 rs17813699 OBFC1 105671857 A G 146 86 15.52 8.1800E-05 10 rs2257791 KIAA1598 118633660 G A 312 222 15.17 9.8300E-05 11 rs1013426 LOC387761 41991781 C T 68 132 20.48 6.0300E-06 11 rs17143894 LOC646195 81995875 T C 38 81 15.54 8.0900E-05 11 rs1790708 LOC646195 82009082 A G 38 81 15.54 8.0900E-05 11 rs10891527 NCAM1 112657000 T C 241 162 15.49 8.3100E-05 11 rs1784394 JAM3 133468426 C T 10 40 18.00 2.2100E-05 12 rs2700141 LOC729507 66273897 T G 365 267 15.20 9.6900E-05 12 rs7306940 NDUFA12 93832224 A G 350 249 17.03 3.6800E-05 12 rs1796016 MED13L 115268994 G A 252 353 16.86 4.0200E-05 13 rs17475847 CRYL1 19806370 T C 190 115 18.44 1.7500E-05 13 rs9567327 FRY 31634085 T C 197 283 15.41 8.6600E-05 13 rs1575900 LOC729485 79574705 G T 222 323 18.72 1.5200E-05 13 rs9545330 LOC729485 79597167 G A 194 288 18.33 1.8600E-05 13 rs942233 LOC729485 79599849 G A 255 352 15.50 8.2500E-05 13 rs1886035 CLYBL 99297374 T C 262 364 16.62 4.5700E-05 14 rs1952790 TTC6 37412427 C T 285 393 17.20 3.3600E-05 14 rs17554993 LOC729122 37508007 T C 290 396 16.38 5.1900E-05
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14 rs7147135 RTN1 59277318 C T 375 275 15.38 8.7700E-05 14 rs6573283 RTN1 59298601 G A 376 273 16.35 5.2800E-05 14 rs2170650 LOC730034 84440848 T C 206 296 16.14 5.9000E-05 15 rs3097531 OCA2 25584546 C A 83 149 18.78 1.4700E-05 15 rs17673470 OCA2 25586078 C T 71 127 15.84 6.9000E-05 15 rs4432234 FAM98B 36521518 G A 275 384 18.03 2.1800E-05 15 rs12905733 FAM98B 36526590 T G 276 382 17.08 3.5900E-05 15 rs17709930 LOC645693 51094957 T C 117 64 15.52 8.1700E-05 15 rs1715937 MNS1 54582191 T C 3 29 21.12 4.3000E-06 16 rs34019675 CTF8 67711441 A G 9 46 24.89 6.0700E-07 16 rs10514391 ZFP1 73762219 T C 47 16 15.25 9.4000E-05 16 rs11649002 ADAMTS18 76090335 A G 135 208 15.54 8.0900E-05 16 rs2880777 NULL 76240765 A G 197 288 17.07 3.6000E-05 17 rs8069536 NTN1 8897010 T G 204 129 16.89 3.9600E-05 17 rs12938262 HRNBP3 74813683 A G 249 348 16.42 5.0800E-05 17 rs4790005 HRNBP3 74820377 T C 246 347 17.20 3.3600E-05 19 rs12974835 CLEC4M 7736930 A G 4 31 20.83 5.0200E-06 19 rs661241 CLEC4GP1 7759053 A G 29 97 36.70 1.3800E-09 20 rs175223 MACROD2 15131893 G A 279 379 15.20 9.6800E-05 20 rs11696476 CBLN4 53398771 A C 306 217 15.15 9.9500E-05 20 rs6089479 CDH4 59710358 G A 215 306 15.89 6.7000E-05 22 rs5765956 ARHGAP8 43529323 C T 404 284 20.93 4.7600E-06
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Supplementary Table 6: Sequencing results for MAFB and ABCA4. Variants without rs # indicate new variants. Coordinates and conservation from http://genome.ucsc.edu. Gene Variant Location AA change Conser-
vation Genotypes in Philippines
Genotypes in Iowa
N Cases
N Controls
N Cases
N Controls
MAFB g. +45025T>C 3' NCC 4/5 80/1/0 88/0/0 89/0/0 87/0/0 g. +44905T>C 3' NCC 7/7 80/0/0 88/0/0 88/1/0 86/1/0 g. +44742A>T 3' NCC 6/6 80/1/0 88/0/0 89/0/0 87/0/0 g. +39089T>C 3' NCC 5/5 59/1/0 88/0/0 89/0/0 ND g. +39060C>T 3' NCC 5/5 59/1/0 ND 89/0/0 ND g. +34277A>G 3' NCC 3/6 39/24/2 51/35/4 89/0/0 90/0/0 g. +34166T>C 3' NCC 6/6 73/2/0 88/1/0 89/0/0 90/0/0 c. *1825G>A 3' NCC 10/10 80/0/0 89/0/0 90/1/0 90/0/0 c. *1743T>C 3' UTR 10/10 80/0/0 ND 76/2/0 ND c. *1721T>C 3' UTR 10/10 80/0/0 ND 76/1/0 ND c. *523G>A 3' UTR 5/8 80/0/0 ND 53/1/0 ND c. *259G>A 3'UTR 4/6 79/1/0 ND 78/0/0 81/0/0 c. *103C>A 3'UTR 7/7 79/1/0 ND 78/0/0 81/0/0 c. *99G>T intron 6/7 73/1/0 88/0/0 78/0/0 81/0/0 c. 745C>A exon 8/8 81/2/0 84/4/0 78/0/0 81/0/0 c. 678C>T exon 8/8 80/0/0 88/0/0 78/0/0 80/1/0 c. 393C>A exon p. His131Gln 6/9 79/4/0 87/1/0 78/0/0 81/0/0 c. 336C>A exon 8/8 81/1/0 88/0/0 78/0/0 81/0/0 c. -169C>A 5'UTR 5/5 79/1/0 ND 78/0/0 ND c. -246C>G 5'UTR 4/4 79/1/0 ND 78/0/0 ND c. -349G>A 5' UTR 3/3 65/15/0 ND 78/0/0 ND g. -76C>T 5'UTR 3/4 79/1/0 ND 78/0/0 ND
g. -157C>T 5'UTR 5/5 78/2/0 ND 57/23/0 ND g. -245C>G 5' UTR NC 74/6/0 ND 64/16/0 ND
ABCA4 rs6666652:G>T exon 49 p.Ser2255Ile NC 82/6/0 ND 67/0/0 ND rs1800555:G>A exon 48 p.Asp2177Asn 4/10 79/0/0 80/0/0 65/1/1 ND rs28938473:C>T exon 48 p.Leu1970Phe 11/11 77/2/0 79/1/0 67/0/0 ND rs56142141:C>T exon 43 p.Pro1948Leu 10/10 80/0/0 ND 43/28/2 ND rs1800552:G>A exon 42 p.Arg1898His 4/10 80/0/0 ND 76/10/1 ND rs1801466:A>T exon 40 p.Asn1868Ile 3/11 80/0/0 ND 80/2/0 ND rs1762111:T>C exon 40 p.Ile1562Thr 9/11 80/0/0 ND 70/8/1 ND
c. 4951G>A exon 33 p. Glu1651Lys 7/12 80/0/0 ND 89/2/0 ND rs61750142:G>A exon 35 p.Arg1443His 10/11 78/2/0 ND 90/0/0 ND rs1800549:C>T exon 29 p.Thr1428Met 10/10 80/1/0 ND 90/0/0 ND
c. 3626T>C exon 29 p. Met1209Thr NC 76/5/0 ND 90/0/0 ND rs61750126:T>G exon 25 p.Leu1201Arg 6/11 89/2/0 ND 90/0/0 ND
c. 3547G>T exon 24 p. Gly1183Cys 8/8 91/0/0 ND 88/1/0 ND rs1801581:G>A exon 24 p.Arg943Gln 6/8 79/10/1 ND 89/0/0 ND
c. 2796G>T exon 19 p. Lys932Asn 7/12 91/0/0 88/0/0 53/4/0 ND rs61754030:A>G exon 19 p. Thr901Ala 6/12 76/1/0 88/0/0 57/0/0 ND
c. 2588G>C exon 18 p. Gly863Ala 8/8 77/0/0 ND 78/2/0 ND c. 1532G>A exon 17 p. Arg511His 11/11 77/0/0 ND 82/1/0 ND
rs3112831:A>G exon 11 p.His423Arg 10/11 77/0/0 ND 85/1/0 ND rs61748549:T>A exon 10 p.Asn380Lys NC ND ND 34/16/2 ND
c. 998G>A exon 9 p. Arg333Gln 10/10 80/1/0 ND 53/1/0 ND c. 682G>A exon 8 p. Ala228Thr 10/11 79/1/0 88/0/0 59/0/0 ND c. 670T>C exon 6 p. Ala224Arg 10/10 79/1/0 88/0/0 59/0/0 ND c. 667A>C exon6 p. Lys223Gln 7/10 79/1/0 88/0/0 59/0/0 ND
rs6657239:G>A exon 6 p.Arg212His 6/11 78/3/0 88/1/0 59/0/0 ND rs61748536:C>G exon 6 p. Ser206Arg 10/10 75/2/0 87/1/0 56/3/0 ND
‘Conservation’ is # of species with nucleotide conserved among total number available. NC: Not conserved. ND: not determined. Bold font denotes missense variants. N of cases/controls indicate common homozygotes/heterozygotes/rare homozygotes.
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Supplementary Table 7: Distribution of MAF for autosomal SNPs among European and Asian parents of CL/P cases European derived Asian derived MAF=0 0<MAF<0.01 0.01<MAF<0.5 Total MAF=0 1330 10106 2792 14228 0<MAF<0.01 340 4854 52793 57987 0.01<MAF<0.5 126 7709 489244 497079 Total 1796 22669 544829 569294
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Legends for Supplementary Figures
Supplementary Figure 1: Principal components analysis based on 33,078 randomly selected, independent SNPs among unrelated parents of cases with an isolated, non-syndromic oral cleft and unrelated individuals from the HapMap Phase II populations (YRI, CEU and CHB/JPT). PC1 accounted for 8.89% of the total genetic variation, while PC2 accounted for 1.57% of the observed genetic variation. Supplementary Figure 2: Q-Q plot for –log10(p-values) of all autosomal SNPs not flagged for QC metrics among 1908 complete CL/P case-parent trios. The gray shaded region indicates 95% confidence band for order statistics. The numbers on the top axis indicate the respective locations for (ordered) expected –log10 p-values. (e.g., the number 1 (10) indicates the expected value, on the –log10 scale, for the minimum (i.e. the tenth smallest) p-value). Clearly visible is a departure from the expected values, beyond what can be explained by random chance Supplementary Figure 3: Estimated OR(case) from a conditional logistic regression and their 95%CI under an additive model for 78 SNPs in chr. 8q24. The minor allele among European parents was the target allele. The most significant SNP (rs987525) is noted by the star. Supplementary Figure 4: Linkage disequilibrium (LD) patterns among parents of European and Asian ancestry (measured as r2) for markers in chr. 8q24 region showing evidence of linkage and association at the genome wide level of significance. The position of rs987525 is noted by the diamond. Supplementary Figure 5: Linkage disequilibrium (LD) patterns among parents of European and Asian ancestry (measured as r2) for markers in MAFB showing evidence of linkage and association at the genome wide level of significance. Supplementary Figure 6: Linkage disequilibrium (LD) patterns among parents of European and Asian ancestry (measured as r2) for markers in ABCA4 showing evidence of linkage and association at genome wide level of significance. Supplementary Figure 7: Comparative amino acid sequence alignment of vertebrate Mafb and location of the conserved H131Q variant found in humans, using amino acid sequences from the Ensembl genome browser (release 56) as aligned by ClustalW.
Nature Genetics: doi:10.1038/ng.580
Supplementary Figure 1: Principal components analysis based on 33,078 randomly selected, independent SNPs among unrelated parents of caseswith an isolated, non-syndromic oral cleft and unrelated individuals from HapMap Phase II populations (YRI, CEU and CHB/JPT). PC1 accounted for 8.89% of the total genetic variation, while PC2 accounted for 1.57% of the observed genetic variation.
Nature Genetics: doi:10.1038/ng.580
Supplementary Figure 2: Q-Q plot for –log10(p-values) of all autosomal SNPs not flagged for QC metrics among 1908 complete CL/P case-parent trios. The gray shaded region indicates 95% confidence band for order statistics. The numbers on the top axis indicate the respective locations for (ordered) expected–log10 p-values. (e.g., the number 1 (10) indicates the expected value, on the –log10 scale, for the minimum (i.e. the tenth smallest) p-value). Clearly visible is a departure from the expected values, beyond what can be explained by random chance.
Nature Genetics: doi:10.1038/ng.580
Supplementary Figure 3: Estimated OR(case) from a conditional logistic regression and their 95%CI under an additive model for 78 SNPs in chr. 8q24. The minor allele among European parents was the target allele. The most significant SNP (rs987525) is noted by the star.
Nature Genetics: doi:10.1038/ng.580
Supplementary Figure 4: Linkage disequilibrium (LD) patterns among parents of European and Asian ancestry (measured as r2) for markers in chr. 8q24 region showing evidence of linkage and association at the genome wide level of significance. The position of rs987525 is noted by the diamond.
Nature Genetics: doi:10.1038/ng.580
Supplementary Figure 5: Linkage disequilibrium (LD) patterns among parents of European and Asian ancestry (measured as r2) for markers in MAFB showing evidence of linkage and association at the genome wide level of significance.
Nature Genetics: doi:10.1038/ng.580
Supplementary Figure 6: Linkage disequilibrium (LD) patterns among parents ofEuropean and Asian ancestry (measured as r2) for markers in ABCA4 showing evidence of linkage and association at genome wide level of significance.
Nature Genetics: doi:10.1038/ng.580
Supplementary Figure 7: Comparative amino acid sequence alignment of vertebrate Mafb and location of the conserved H131Q variant found in humans, using amino acid sequences from the Ensembl genome browser (release 56) as aligned by ClustalW.
Nature Genetics: doi:10.1038/ng.580
