Yongchen Hao Xuehui Liu Xiangfeng Lu Xueli Yang Laiyuan Wang

Genome-wide association study in Han Chinese identifies three novel loci for human height Supplemental Material

Genome-wide association study in Han Chinese identifies three novel loci for human height Yongchen Hao · Xuehui Liu · Xiangfeng Lu · Xueli Yang · Laiyuan Wang · Shufeng Chen · Hongfan Li · Jianxin Li · Jie Cao · Jichun Chen · Ying Li · Liancheng Zhao · Yongyong Shi · Chong Shen · Weili Yan · Jiang He · Jianfeng Huang · Dongfeng Gu

Y. Hao · X. Liu · X. Lu (✉) · X. Yang · L. Wang · S. Chen · H. Li · J. Li · J. Cao · J. Chen · Y. Li · L. Zhao · J. Huang · D. Gu (✉) State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China E-mail (X. Lu): [email protected] E-mail (D. Gu): [email protected] Tel: +86 (10) 68331752 Fax: +86 (10) 88363812

L. Wang · H. Li National Human Genome Center at Beijing, Beijing, China

Y. Shi Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.

C. Shen Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China

W. Yan Division of Clinical Epidemiology, Pediatric Institute, Children’s Hospital of Fudan University, Shanghai, China

J. He Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA

Y. Hao and X. Liu contributed equally to this work. Supplementary Table 1 Main characteristic of subjects

Population Gender Number of Age/year Height/cm subjects CAS case Male 853 49.7(7.7) 171.2(5.5) Female 157 55.9(7.5) 159.2(4.9) CAS control Male 1870 52.7(7.7) 167.6(6.0) Female 2128 52.4(7.7) 155.9(5.9) BAS case Male 430 51.7(8.7) 168.9(5.9) Female 75 55.4(7.3) 155.0(5.8) BAS control Male 757 55.8(8.4) 168.0 (5.8) Female 264 61.7(8.5) 156.4(6.0) GenSalt Male 993 39.3(9.6) 167.8(5.7) Female 888 38.1(9.4) 157.0(5.1) Data are presented as mean (SD). Supplementary Table 2 Associations of the previously reported SNP in our discovery study (P<0.05)

SNP Nearest gene Chr Position(BP)a Effect/ Frequency of Effect SE P-value Reference other allele effect allele sizeb rs4601530 CLIC4 1 24,916,698 T/C 0.43 - 0.01 1.00E-02 Lango Allen et al. (2010) 0.047 8 rs9428104 SPAG17 1 118,657,110 A/G 0.36 - 0.01 4.10E-04 Lango Allen et al. (2010) 0.065 8 rs3791675 EFEMP1 2 55,964,813 T/C 0.78 - 0.02 4.32E-04 Weedon et al. (2008) 0.074 1 rs11684404 EIF2AK3 2 88,705,737 T/C 0.54 - 0.01 7.44E-03 Lango Allen et al. (2010) 0.047 8 rs7571816 DIS3L2 2 232,785,308 A/G 0.48 0.058 0.01 9.50E-04 Sanna et al. (2008) 8 rs7678436 NCAPG- 4 17,407,064 A/G 0.29 - 0.02 5.52E-04 Gudbjartsson et al. (2008) LCORL 0.077 2 rs17081935 POLR2B 4 57,518,233 T/C 0.39 0.042 0.01 1.98E-02 Lango Allen et al. (2010) 8 rs955748 WWC2 4 184,452,669 A/G 0.41 - 0.01 2.16E-02 Lango Allen et al. (2010) 0.042 8 rs3812163 BMP6 6 7,670,759 A/T 0.79 - 0.02 1.89E-02 Lango Allen et al. (2010) 0.050 1 rs806794 Histone cluster 6 26,308,656 A/G 0.27 0.078 0.02 6.49E-04 Lango Allen et al. (2010) 3 rs2256183 MICA 6 31,488,508 A/G 0.25 0.048 0.02 2.48E-02 Lango Allen et al. (2010) 2 rs7759938 LIN28B 6 105,485,647 T/C 0.72 - 0.02 4.45E-02 Lango Allen et al. (2010) 0.041 0 rs1046943 ZBTB24 6 109,890,634 A/G 0.51 0.041 0.01 3.49E-02 Lango Allen et al. (2010) 9 rs1490384 C6orf173 6 126,892,853 T/C 0.98 0.126 0.06 3.65E-02 Lango Allen et al. (2010) 0 rs6569648 L3MBTL3 6 130,390,812 T/C 0.94 - 0.03 3.23E-02 Lango Allen et al. (2010) 0.077 6 rs7763064 GPR126 6 142,838,982 A/G 0.32 - 0.02 1.18E-02 Lango Allen et al. (2010) 0.049 0 rs6959212 STARD3NL 7 38,094,851 T/C 0.33 - 0.01 3.25E-02 Lango Allen et al. (2010) 0.040 9 rs7460090 SDR16C5 8 57,356,717 T/C 0.96 0.091 0.04 4.36E-02 Lango Allen et al. (2010) 5 rs11144688 PCSK5 9 77,732,106 A/G 0.05 -0.119 0.04 5.00E-03 Lango Allen et al. (2010) 2 rs10512248 PTCH1 9 97,299,524 T/G 0.67 - 0.01 1.35E-02 Weedon et al. (2008) 0.046 9 rs12338076 QSOX2 9 138,261,561 A/C 0.68 - 0.02 3.42E-02 Lango Allen et al. (2010) 0.047 2 rs494459 TREH 11 118,079,885 T/C 0.42 0.059 0.01 1.01E-03 Lango Allen et al. (2010) 8 rs11107116 SOCS2 12 92,502,635 T/G 0.32 0.044 0.01 1.87E-02 Weedon et al. (2008) 9 rs7319045 GPC5 13 90,822,575 A/G 0.47 0.052 0.01 3.02E-03 Lango Allen et al. (2010) 8 rs2093210 SIX6 14 60,027,032 T/C 0.27 - 0.02 3.12E-02 Lango Allen et al. (2010) 0.043 0 rs7153027 FBLN5 14 91,496,975 A/C 0.73 0.071 0.02 3.25E-04 Gudbjartsson et al. (2008) 0 rs7155279 TRIP11 14 91,555,634 T/G 0.32 - 0.01 8.84E-04 Lango Allen et al. (2010) 0.064 9 rs16964211 CYP19A1 15 49,317,787 A/G 0.25 - 0.02 2.31E-04 Lango Allen et al. (2010) 0.075 0 rs2871865 IGF1R 15 97,012,419 C/G 0.94 0.130 0.03 2.84E-04 Lango Allen et al. (2010) 6 rs4533267 ADAMTS17 15 98,603,794 A/G 0.19 0.052 0.02 1.87E-02 Gudbjartsson et al. (2008) 2 rs1787200 DYM 18 44,841,652 A/G 0.61 0.044 0.01 1.39E-02 Weedon et al. (2008) 8 rs17782313 MC4R 18 56,002,077 T/C 0.78 - 0.02 1.86E-03 Lango Allen et al. (2010) 0.065 1 rs967417 BMP2 20 6,568,893 A/G 0.79 - 0.02 3.86E-02 Gudbjartsson et al. (2008) 0.044 2 rs6060369 UQCC 20 33,370,575 T/C 0.73 - 0.01 2.92E-05 Lettre et al. (2008) 0.081 9 rs237743 ZNFX1 20 47,336,426 A/G 0.05 0.101 0.04 1.75E-02 Lango Allen et al. (2010) 3 a Information for SNP ID and chromosomal position is based on NCBI genome build 36. b Effect size represented the difference in height Z-score associated with each additional allele and was estimated for effect allele. Supplementary Fig. 1 Q-Q plots of the genome-wide association results

The observed P values (y-axis) were compared with the expected chi-squared values under the null distribution (x-axis). The QQ-plot includes all SNPs that passed the inclusion criteria. The 95% confidence interval of expected values is indicated in grey. Supplementary Fig. 2 LD patterns of the region on 15q21.2 in populations of Chinese and European ancestry The LD patterns were created using the Haploview software and the genotyping data from the HapMap project. The upper panel shows the D’ pattern in European-descent population and the bottom panel shows the D’ pattern in the Chinese population. References Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, den Heijer M, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K (2008) Many sequence variants affecting diversity of adult human height. Nat Genet 40: 609-615 Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segre AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Magi R, Pastinen T, Liang L, Heid IM, Luan J, Thorleifsson G, Winkler TW, Goddard ME, Sin Lo K, Palmer C, Workalemahu T, Aulchenko YS, Johansson A, Zillikens MC, Feitosa MF, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer NL, Hayward C, Hottenga JJ, Jacobs KB, Knowles JW, Kutalik Z, Monda KL, Polasek O, Preuss M, Rayner NW, Robertson NR, Steinthorsdottir V, Tyrer JP, Voight BF, Wiklund F, Xu J, Zhao JH, Nyholt DR, Pellikka N, Perola M, Perry JR, Surakka I, Tammesoo ML, Altmaier EL, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman DI, Chen C, Coin L, Cooper MN, Dixon AL, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan LM, Kettunen J, Konig IR, Kwan T, Lawrence RW, Levinson DF, Lorentzon M, McKnight B, Morris AP, Muller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E, et al. (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467: 832-838 Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Boehnke M, Chanock SJ, Groop LC, Hu FB, Isomaa B, Kraft P, Peltonen L, Salomaa V, Schlessinger D, Hunter DJ, Hayes RB, Abecasis GR, Wichmann HE, Mohlke KL, Hirschhorn JN (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40: 584-591 Sanna S, Jackson AU, Nagaraja R, Willer CJ, Chen WM, Bonnycastle LL, Shen H, Timpson N, Lettre G, Usala G, Chines PS, Stringham HM, Scott LJ, Dei M, Lai S, Albai G, Crisponi L, Naitza S, Doheny KF, Pugh EW, Ben-Shlomo Y, Ebrahim S, Lawlor DA, Bergman RN, Watanabe RM, Uda M, Tuomilehto J, Coresh J, Hirschhorn JN, Shuldiner AR, Schlessinger D, Collins FS, Davey Smith G, Boerwinkle E, Cao A, Boehnke M, Abecasis GR, Mohlke KL (2008) Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40: 198-203 Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JR, Stevens S, Hall AS, Samani NJ, Shields B, Prokopenko I, Farrall M, Dominiczak A, Johnson T, Bergmann S, Beckmann JS, Vollenweider P, Waterworth DM, Mooser V, Palmer CN, Morris AD, Ouwehand WH, Zhao JH, Li S, Loos RJ, Barroso I, Deloukas P, Sandhu MS, Wheeler E, Soranzo N, Inouye M, Wareham NJ, Caulfield M, Munroe PB, Hattersley AT, McCarthy MI, Frayling TM (2008) Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40: 575-583