A Genome-wide Association Study in Han Chinese Identifies Multiple. Susceptibility loci for IgA Nephropathy. Supplementary Material

A Genome-wide Association Study in Han Chinese Identifies Multiple Susceptibility loci for IgA Nephropathy Supplementary Material Xue-Qing Yu 1,13, Ming Li 1,13, Hong Zhang 2,13, Hui-Qi Low 3, Xin Wei 1, Jin-Quan Wang 4, Liang-Dan Sun 5, Kar-Seng Sim 3, Yi Li 3, Jia-Nee Foo 3, Wei Wang 1, Zhi-Jian Li 1, Xian-Yong Yin 5, Xue-Qing Tang 1, Li Fan 1, Jian Chen 6, Rong-Shan Li 7, Jian-Xin Wan 8, Zhang-Suo Liu 9, Tan-Qi Lou 10, Li Zhu 2, Xiao-Jun Huang 11, Xue-Jun Zhang 5, Zhi-Hong Liu 4, Jian-Jun Liu 3,12 Correspondence should be addressed to: Dr. Xue-Qing Yu at The Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University; Key Laboratory of Nephrology, Ministry of Health, Guangzhou, 510080, P. R. China, or at yuxq@mail.sysu.edu.cn Dr. Jian-Jun Liu at the Department of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore; School of Biological Sciences, Anhui Medical University, Hefei, Anhui, 230032, China; or at liuj3@gis.a-star.edu.sg The authors affiliations are as follows: 1. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Nephrology, Ministry of Health, Guangzhou, Guangdong, China 2. Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Beijing, China 3. Human Genetics, Genome Institute of Singapore, Singapore 1

4. Department of Nephrology, Nanjing General Hospital of Nanjing Military Command, Nanjing, Jiangsu, China 5. Institute of Dermatology and Department of Dermatology, No.1 Hospital, Anhui Medical University, Hefei, Anhui, China; State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, Anhui, China; 6. Department of Nephrology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, Fujian, China 7. Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China 8. Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China 9. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 10. Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 11. Department of Hematology, Peking University People's Hospital, Beijing, China; 12. School of Life Sciences, Anhui Medical University, Hefei, Anhui, China 13. These authors contributed equally to the work 2

Supplementary table 1 Stepwise conditional analysis of association among the signals within the HLA region in the discovery cohort Test SNP conditioning SNP(s) GWAS (1434 cases /4270controls) Unconditioned Conditioned OR P OR P rs2523946 0.77 4.05E-09 NA NA rs9264942 0.78 8.24E-08 0.79 1.93E-07 rs660895 rs2523946 1.29 8.19E-08 1.25 5.28E-06 rs1794275 1.38 3.28E-08 1.36 2.32E-07 rs9277554 1.19 1.46E-04 1.21 4.65E-05 rs2523946 0.77 4.05E-09 NA NA rs9264942 0.78 8.24E-08 NA NA rs2523946, rs660895 1.29 8.19E-08 1.24 8.51E-06 rs9264942 rs1794275 1.38 3.28E-08 1.33 1.79E-06 rs9277554 1.19 1.46E-04 1.24 4.34E-06 rs2523946 0.77 4.05E-09 NA NA rs9264942 rs2523946, 0.78 8.24E-08 NA NA rs660895 rs9264942, 1.29 8.19E-08 1.2 2.86E-04 rs1794275 rs1794275 1.38 3.28E-08 NA NA rs9277554 1.19 1.46E-04 1.26 7.82E-07 rs2523946 0.77 4.05E-09 NA NA rs9264942 rs2523946, 0.78 8.24E-08 NA NA rs9264942, rs660895 1.29 8.19E-08 1.22 4.86E-05 rs1794275, rs1794275 rs9277554 1.38 3.28E-08 NA NA rs9277554 1.19 1.46E-04 NA NA 3

Supplementary table 2 Stepwise conditional analysis among three significant SNPs within the HLA region in both discovery and replication samples Test SNP Conditioning SNPs All (4137cases/7734controls) Unconditioned Conditioned OR P OR P rs2523946 1.21 1.74E-11 1.17 8.14E-08 rs660895 rs660895 1.34 4.13E-20 NA NA rs1794275 1.30 3.43E-13 1.22 1.13E-07 rs2523946 1.21 1.74E-11 NA NA rs660895, rs660895 1.34 4.13E-20 NA NA rs2523946 rs1794275 1.30 3.43E-13 1.21 3.46E-07 4

Supplementary table 3 Haplotype frequencies and associations of 3 validated MHC SNPs in the combined GWAS and validation samples Freq Haplotype* All samples Cases Controls OR P TAG 0.405 0.370 0.424 0.75 8.54E-21 CAG 0.269 0.263 0.272 0.97 2.81E-01 CGG 0.127 0.138 0.121 1.24 4.46E-07 CGA 0.063 0.077 0.056 1.47 9.70E-12 CAA 0.049 0.056 0.045 1.17 1.36E-02 TGG 0.039 0.041 0.038 1.13 8.77E-02 TAA 0.025 0.028 0.024 1.05 6.00E-01 TGA 0.024 0.029 0.021 1.34 7.41E-04 *Haplotype SNPs: rs2523946 rs660895 rs1794275 5

Supplementary Table 4 Association analysis of the 7 validated SNPs using normal controls vs. clinical verified controls and with vs. without age and gender adjustment 4137 cases Vs. Minor 7734controls 2535 Clinically verified controls 3801 cases/7587 Controls CHR SNP Position allele OR (95%CI) OR (95%CI) P_Heterogeneity OR (95%CI) P OR (95%CI)* P* 6 rs2523946 30049922 C 1.21(1.15-1.28) 1.14(1.04-1.23) 0.22 1.21(1.14-1.28) 1.96E-10 1.16(1.10-1.23) 5.7E-08 6 rs660895 32685358 G 1.34(1.26-1.42) 1.22(1.11-1.34) 0.13 1.35(1.27-1.44) 1.04E-19 1.27(1.20-1.35) 4.8E-15 6 rs1794275 32779226 A 1.30(1.21-1.39) 1.31(1.17-1.46) 0.92 1.29(1.20-1.39) 1.14E-11 1.33(1.24-1.43) 3.5E-16 8 rs2738048 6810195 G 0.79(0.74-0.84) 0.81(0.74-0.88) 0.69 0.79(0.75-0.85) 1.08E-12 0.79(0.75-0.84) 2.2E-14 17 rs3803800 7403693 A 1.21(1.14-1.28) 1.16(1.06-1.26) 0.38 1.21(1.14-1.28) 8.17E-10 1.16(1.10-1.23) 1.8E-07 17 rs4227 7431901 G 1.23(1.16-1.32) 1.16(1.05-1.28) 0.31 1.24(1.16-1.33) 8.56E-10 1.18(1.11-1.26) 2.9E-07 22 rs12537 28753460 T 0.78(0.72-0.84) 0.76(0.68-0.84) 0.70 0.79(0.73-0.85) 3.66E-10 0.82(0.77-0.88) 6.7E-08 *Adjusted for age and gender 6

Supplementary Table 5 The association results of the 54 SNPs in the GWAS, replication and combined samples GWAS Replication (2703 cases/3464controls) All (1434 Cases/4270 Controls) Replication 1 (1402/1716) replication 2(1301/1748) Combined(2703/3464) (4137cases/7734controls) SNP CHR Gene MA* P OR 95%CI P OR 95%CI P OR 95%CI P OR 95%CI P OR 95%CI I 2 Q ** rs10799801 1 x G 8.10E-05 0.71 0.60 0.84 2.86E-01 1.13 0.91 1.40 1.84E-01 1.14 0.94 1.39 8.71E-02 1.14 0.98 1.31 1.58E-01 0.92 0.83 1.03 0.88 2.15E-04 rs2421787 1 x G 3.96E-05 0.83 0.76 0.91 2.08E-01 1.07 0.96 1.18 8.16E-01 1.01 0.92 1.12 2.85E-01 1.04 0.97 1.12 7.24E-02 0.95 0.90 1.01 0.87 4.51E-04 rs11579502 1 x C 5.51E-05 0.81 0.73 0.90 7.31E-01 1.02 0.91 1.14 7.76E-01 1.02 0.91 1.14 6.60E-01 1.02 0.94 1.10 2.72E-02 0.93 0.88 0.99 0.83 2.69E-03 rs7518801 1 x C 1.46E-07 1.29 1.17 1.42 5.26E-01 0.96 0.85 1.09 1.35E-01 0.91 0.81 1.03 1.33E-01 0.94 0.86 1.02 1.99E-02 1.08 1.01 1.15 0.92 4.50E-06 rs2477106 1 CEP350 G 7.14E-05 0.80 0.71 0.89 2.90E-01 1.07 0.95 1.21 5.45E-01 1.04 0.91 1.18 2.35E-01 1.06 0.97 1.15 1.04E-01 0.94 0.88 1.01 0.87 6.01E-04 rs2085261 1 x T 2.67E-05 1.21 1.11 1.32 4.56E-01 0.96 0.87 1.07 3.95E-03 0.86 0.77 0.95 1.08E-02 0.91 0.85 0.98 4.90E-01 1.02 0.96 1.08 0.92 2.20E-06 rs4438515 2 x T 9.57E-05 1.19 1.09 1.30 2.65E-01 0.94 0.85 1.05 4.41E-01 0.96 0.87 1.07 1.84E-01 0.95 0.89 1.02 1.39E-01 1.04 0.99 1.10 0.87 5.88E-04 rs11903923 2 PRKCE T 1.78E-05 1.28 1.14 1.44 5.98E-01 1.04 0.90 1.19 1.74E-01 0.91 0.79 1.04 5.49E-01 0.97 0.88 1.07 2.21E-02 1.09 1.01 1.17 0.87 5.50E-04 rs4849121 2 ACOXL G 6.83E-05 1.19 1.09 1.30 3.81E-02 1.11 1.01 1.23 1.01E-02 1.14 1.03 1.26 8.93E-04 1.13 1.05 1.21 4.08E-07 1.15 1.09 1.22 0.00 5.51E-01 rs2625956 3 H1FOO T 1.85E-05 0.82 0.75 0.90 6.18E-01 1.03 0.93 1.14 9.21E-01 1.01 0.90 1.12 6.70E-01 1.02 0.94 1.09 1.65E-02 0.93 0.88 0.99 0.85 1.45E-03 rs6832151 4 x G 9.95E-07 1.25 1.14 1.36 3.95E-01 1.05 0.94 1.16 7.83E-01 1.02 0.92 1.12 4.25E-01 1.03 0.96 1.11 1.85E-04 1.11 1.05 1.18 0.81 4.70E-03 rs10518159 4 x T 3.14E-10 1.63 1.40 1.89 5.42E-01 0.93 0.74 1.17 8.45E-01 1.02 0.82 1.27 7.84E-01 0.98 0.84 1.15 2.23E-05 1.27 1.14 1.42 0.90 2.76E-05 rs4286636 5 x C 8.96E-05 1.38 1.17 1.61 1.17E-02 0.78 0.64 0.95 5.40E-01 0.94 0.77 1.15 2.45E-02 0.85 0.74 0.98 4.40E-01 1.04 0.94 1.16 0.91 2.47E-05 rs3757261 6 SIRT5 T 3.98E-05 1.26 1.13 1.41 1.44E-01 0.90 0.77 1.04 8.05E-01 0.98 0.86 1.13 2.45E-01 0.94 0.85 1.04 6.84E-02 1.07 0.99 1.15 0.87 4.20E-04 rs10948800 6 RANBP9 G 1.70E-05 1.23 1.12 1.35 8.24E-01 0.99 0.87 1.12 6.04E-01 1.03 0.92 1.16 8.19E-01 1.01 0.93 1.10 2.55E-03 1.10 1.04 1.17 0.79 8.09E-03 rs9393692 6 x A 4.32E-06 0.69 0.59 0.81 1.86E-01 0.90 0.77 1.05 4.23E-01 1.07 0.90 1.28 6.50E-01 0.97 0.87 1.09 1.25E-03 0.86 0.78 0.94 0.86 8.85E-04 rs845858 6 x G 6.19E-05 0.82 0.74 0.90 8.28E-01 1.01 0.90 1.14 6.27E-01 0.97 0.87 1.09 8.46E-01 0.99 0.92 1.08 6.41E-03 0.92 0.86 0.98 0.78 1.06E-02 rs9322538 6 x G 4.73E-05 1.22 1.11 1.34 3.68E-01 1.05 0.94 1.17 8.77E-02 0.90 0.80 1.02 6.13E-01 0.98 0.90 1.06 2.80E-02 1.07 1.01 1.14 0.87 4.84E-04 rs9264942 6 x C 8.2E-08 0.78 0.72 0.86 7.98E-01 1.01 0.92 1.12 8.88E-01 0.99 0.89 1.10 9.21E-01 1.00 0.93 1.08 7.64E-04 0.91 0.86 0.96 0.89 1.41E-04 rs9277554 6 x C 1.46E-04 1.19 1.09 1.31 9.37E-01 1.00 0.91 1.11 4.36E-01 1.04 0.94 1.16 5.40E-01 1.02 0.95 1.10 4.56E-03 1.09 1.03 1.15 0.71 3.02E-02 rs4590341 7 BBS9 A 2.75E-05 1.20 1.10 1.31 4.30E-02 1.11 1.00 1.23 9.15E-01 1.01 0.91 1.12 1.32E-01 1.06 0.98 1.14 1.17E-04 1.12 1.06 1.18 0.71 3.31E-02 7

rs2188404 7 CCDC132 C 1.28E-07 0.78 0.71 0.86 2.72E-01 1.06 0.96 1.17 5.03E-01 1.04 0.93 1.15 2.11E-01 1.05 0.97 1.13 1.77E-02 0.93 0.88 0.99 0.92 5.66E-06 rs4451226 7 x T 4.61E-05 0.76 0.67 0.87 4.13E-01 1.07 0.91 1.26 4.89E-02 1.16 1.00 1.35 4.46E-02 1.12 1.00 1.25 2.32E-01 0.95 0.87 1.03 0.90 4.61E-05 rs6459896 7 x G 9.26E-05 0.84 0.77 0.92 8.61E-01 1.01 0.91 1.12 4.44E-01 0.96 0.87 1.07 6.79E-01 0.98 0.91 1.06 4.99E-03 0.92 0.87 0.98 0.75 1.74E-02 rs10283337 8 x G 4.95E-05 0.83 0.76 0.91 6.68E-01 0.98 0.88 1.08 5.76E-01 1.03 0.93 1.14 9.33E-01 1.00 0.93 1.08 1.14E-02 0.93 0.88 0.98 0.81 4.86E-03 rs17054017 8 x A 2.46E-05 1.31 1.16 1.48 1.07E-01 0.88 0.75 1.03 9.89E-01 1.00 0.85 1.18 2.58E-01 0.94 0.84 1.05 5.31E-02 1.09 1.00 1.18 0.88 2.72E-04 rs12541729 8 x C 3.19E-05 0.82 0.74 0.90 2.48E-01 0.94 0.85 1.04 6.90E-01 0.98 0.88 1.09 2.66E-01 0.96 0.89 1.03 5.38E-04 0.90 0.85 0.96 0.71 3.05E-02 rs2874041 8 PTDSS1 T 5.67E-05 0.83 0.76 0.91 5.03E-01 0.97 0.87 1.07 5.20E-01 0.97 0.87 1.07 3.50E-01 0.97 0.90 1.04 1.09E-03 0.91 0.86 0.96 0.69 3.88E-02 rs614541 9 x T 7.95E-05 1.21 1.10 1.32 6.95E-01 0.98 0.88 1.09 9.89E-01 1.00 0.90 1.12 7.88E-01 0.99 0.92 1.07 2.18E-02 1.07 1.01 1.14 0.81 5.65E-03 rs3780193 9 PSAT1 A 5.98E-05 1.21 1.10 1.32 8.89E-01 1.01 0.91 1.12 4.95E-01 1.04 0.93 1.16 5.61E-01 1.02 0.95 1.10 2.71E-03 1.09 1.03 1.16 0.73 2.32E-02 rs370415 10 x C 7.93E-05 1.37 1.17 1.60 8.70E-01 0.98 0.81 1.19 3.70E-01 1.10 0.89 1.35 6.21E-01 1.04 0.90 1.19 3.16E-03 1.17 1.06 1.30 0.73 2.61E-02 rs10824274 10 DUSP13 C 7.84E-05 1.20 1.09 1.31 8.15E-01 0.99 0.90 1.09 6.27E-01 1.03 0.92 1.14 8.68E-01 1.01 0.94 1.08 9.18E-03 1.08 1.02 1.14 0.78 1.09E-02 rs7895560 10 x A 3.90E-05 1.27 1.13 1.42 3.42E-01 0.94 0.82 1.07 9.13E-01 0.99 0.87 1.14 4.61E-01 0.97 0.88 1.06 4.33E-02 1.08 1.00 1.16 0.85 1.15E-03 rs7127924 11 x A 1.74E-05 1.23 1.12 1.35 2.12E-01 1.07 0.96 1.18 3.59E-01 1.05 0.95 1.17 1.13E-01 1.06 0.99 1.15 1.24E-04 1.12 1.06 1.19 0.67 4.99E-02 rs17157266 11 x C 2.16E-06 1.27 1.15 1.40 3.94E-01 0.96 0.86 1.06 5.31E-01 0.97 0.86 1.08 2.92E-01 0.96 0.89 1.04 4.10E-02 1.07 1.00 1.13 0.90 6.67E-05 rs12787940 11 x A 5.22E-05 1.32 1.16 1.52 1.77E-01 0.89 0.75 1.06 5.11E-01 0.95 0.80 1.12 1.60E-01 0.92 0.82 1.03 1.29E-01 1.07 0.98 1.17 0.88 3.31E-04 rs10488764 11 FDX1 A 7.15E-05 1.22 1.10 1.34 6.17E-01 1.03 0.92 1.15 5.69E-01 1.03 0.92 1.15 4.45E-01 1.03 0.95 1.12 2.03E-03 1.10 1.04 1.17 0.70 3.52E-02 rs897685 11 x C 1.82E-09 1.48 1.30 1.69 9.16E-01 0.99 0.84 1.17 8.52E-01 1.02 0.85 1.21 9.60E-01 1.00 0.89 1.13 5.42E-05 1.20 1.10 1.31 0.90 7.23E-05 rs2159963 12 x T 7.85E-06 1.24 1.13 1.36 5.61E-01 0.97 0.87 1.08 9.32E-02 0.91 0.82 1.02 1.10E-01 0.94 0.87 1.01 1.10E-01 1.05 0.99 1.11 0.90 3.52E-05 rs4485187 12 x G 1.23E-05 1.21 1.11 1.32 1.71E-01 1.07 0.97 1.19 8.96E-01 1.01 0.91 1.12 2.85E-01 1.04 0.97 1.12 3.09E-04 1.11 1.05 1.17 0.75 1.86E-02 rs7299302 12 AEBP2 T 4.95E-05 1.23 1.11 1.36 4.57E-01 0.96 0.85 1.08 3.79E-01 1.06 0.94 1.19 9.28E-01 1.00 0.92 1.09 6.92E-03 1.09 1.03 1.17 0.81 5.60E-03 rs1463739 12 x G 1.21E-07 0.75 0.67 0.83 2.16E-01 1.08 0.96 1.21 7.04E-01 1.02 0.91 1.15 2.52E-01 1.05 0.97 1.14 1.66E-02 0.92 0.87 0.99 0.92 4.85E-06 rs17781793 12 x G 2.57E-06 1.60 1.32 1.95 6.02E-01 0.94 0.76 1.17 3.18E-01 0.88 0.69 1.13 2.88E-01 0.92 0.78 1.08 4.42E-02 1.14 1.00 1.29 0.89 8.78E-05 rs8181764 12 x C 4.59E-05 0.83 0.77 0.91 4.63E-01 0.96 0.87 1.07 4.75E-01 0.96 0.87 1.07 2.98E-01 0.96 0.89 1.04 6.84E-04 0.91 0.86 0.96 0.68 4.51E-02 rs4883688 13 x T 3.77E-05 0.80 0.72 0.89 2.63E-01 0.94 0.83 1.05 8.01E-01 1.02 0.90 1.15 5.21E-01 0.97 0.89 1.06 1.70E-03 0.90 0.84 0.96 0.77 1.25E-02 rs6573893 14 x C 4.60E-05 1.25 1.12 1.39 1.92E-01 1.08 0.96 1.23 6.19E-01 1.03 0.91 1.17 1.92E-01 1.06 0.97 1.16 3.71E-04 1.13 1.06 1.21 0.65 5.90E-02 rs1008507 15 IQGAP1 T 8.64E-05 0.63 0.50 0.79 5.28E-01 0.93 0.76 1.16 1.09E-01 1.21 0.96 1.53 5.40E-01 1.05 0.90 1.23 5.76E-02 0.88 0.78 1.00 0.87 4.23E-04 8

rs3925075 16 x A 6.67E-05 0.82 0.75 0.91 7.25E-01 0.98 0.87 1.10 1.28E-03 0.83 0.75 0.93 8.69E-03 0.90 0.83 0.97 4.64E-06 0.87 0.81 0.92 0.64 6.12E-02 rs2639311 16 x T 4.92E-05 1.28 1.14 1.44 9.17E-01 0.99 0.86 1.15 9.58E-01 1.00 0.87 1.15 9.11E-01 0.99 0.90 1.10 1.24E-02 1.10 1.02 1.19 0.80 6.67E-03 rs905780 16 WWOX T 7.20E-05 0.80 0.71 0.89 1.77E-01 0.91 0.80 1.04 9.16E-01 1.01 0.88 1.15 3.85E-01 0.96 0.87 1.05 1.04E-03 0.89 0.83 0.95 0.72 2.75E-02 rs9652852 17 x T 3.45E-05 0.83 0.76 0.91 6.93E-01 0.98 0.88 1.09 2.87E-01 1.06 0.95 1.17 6.41E-01 1.02 0.95 1.10 2.26E-02 0.94 0.89 0.99 0.85 1.29E-03 rs12964637 18 x G 4.35E-05 0.83 0.76 0.91 5.59E-01 1.03 0.93 1.14 1.45E-01 0.93 0.84 1.03 5.30E-01 0.98 0.91 1.05 2.32E-03 0.92 0.87 0.97 0.80 6.57E-03 rs2109541 18 x A 8.62E-06 0.81 0.74 0.89 3.84E-01 1.05 0.94 1.17 5.65E-01 0.97 0.87 1.08 8.43E-01 1.01 0.94 1.09 7.96E-03 0.92 0.87 0.98 0.86 9.09E-04 rs2825311 21 x T 7.81E-05 0.61 0.48 0.78 3.81E-01 0.90 0.70 1.15 5.45E-01 1.09 0.83 1.41 8.19E-01 0.98 0.82 1.17 6.58E-03 0.82 0.71 0.95 0.81 5.45E-03 * MA = minor allele replication 1:Northern Samples replication 2:Southern Samples **Q: P value for the Cochran's Q statistic 9

Supplementary table 6 The allele frequency and the QC result (R 2 and Call Rate) of the imputed classical HLA alleles and stepwise conditional analysis of the HLA alleles in the discovery cohort HLA alleles GWAS Allele Freq (1434 cases /4270controls) R 2 conditioning Call Rate HLA allele(s) unconditioned conditioned Cases Controls OR P OR P HLA-B*4001 0.192 0.161 0.976 0.975 1.34 5.64E-07 NA NA HLA-DQB*0302 0.09 0.074 0.792 0.954 HLA-B*4001 1.43 4.07E-05 1.42 7.53E-05 HLA-A*1101 0.35 0.297 0.967 0.975 1.23 1.27E-05 1.2 1.18E-04 HLA-B*4001 0.192 0.161 0.976 0.975 1.34 5.64E-07 NA NA HLA-B*4001, HLA-DQB*0302 0.09 0.074 0.792 0.954 1.43 4.07E-05 NA NA HLA-DQB*0302 HLA-A*1101 0.35 0.297 0.967 0.975 1.23 1.27E-05 1.19 4.01E-04 R 2 : the estimated squared correlation (0 R 2 1) between the most likely imputed allele dosage (with highest posterior probability) and the true allele dosage; call rate: percentage of the samples that could be imputed if a genotype probability of 90% was used as a minimal threshold for accepting an imputed genotype. 10

Supplementary Table 7 The association results of HLA allele haplotypes HLA- haplotype freq OR P Cases Controls HLA-DQA*0201-DQB*0201 0.028 0.046 0.595 3.84E-05 HLA-B*4001-DQB*0302 0.021 0.012 1.964 5.68E-05 HLA-DRB*0901-DQB*0303 0.120 0.154 0.766 6.01E-05 HLA-A*1101-DQB*0302 0.036 0.026 1.538 5.38E-04 HLA-A*3303-DQB*0201 0.031 0.047 0.659 6.57E-04 HLA-A*1101-B*4001 0.081 0.068 1.287 2.34E-03 HLA-A*1101-DQB*0303 0.041 0.048 0.839 1.03E-01 HLA-A*3303-DQB*0302 0.004 0.002 1.870 1.13E-01 HLA-A*1101-DQB*0201 0.012 0.013 0.867 4.77E-01 HLA-A*1101-B*4001-DQB*0302 0.010 0.005 2.094 3.16E-03 HLA-B*4001-DRB*0901-DQB*0303 0.014 0.023 0.646 1.35E-02 HLA-A*1101-DRB*0901-DQB*0303 0.032 0.043 0.752 1.76E-02 HLA-A*3303-DQA*0201-DQB*0201 0.001 0.004 0.315 3.04E-02 HLA-A*3303-DRB*0901-DQB*0303 0.002 0.005 0.504 9.63E-02 HLA-A*1101-DQA*0201-DQB*0201 0.004 0.005 0.640 1.78E-01 11

Supplementary table 8 Conditional analysis of rs9275596 and the haplotypes of 3 validated MHC SNPs Haplotype or SNP Conditioning P OR 95% CI TAG <2.0E-16 0.67 0.61 0.74 CGG 5.62E-04 1.24 1.10 1.41 CGA 3.00E-03 1.35 1.11 1.65 TGA 1.67E-01 1.20 0.93 1.54 rs9275596 1.65E-08 0.68 1.29 1.70 TAG rs9275596 1.89E-12 0.70 0.64 0.78 CGG rs9275596 1.00E-02 1.18 1.04 1.34 CGA rs9275596 1.30E-02 1.29 1.06 1.57 TGA rs9275596 3.03E-01 1.14 0.89 1.47 rs9275596 4 haplotypes 2.06E-03 0.78 0.68 0.90 association analyses were performed in 1434cases and 4270 controls of the GWAS sample 12

Supplementary table 9 The association results of the 2 reported SNPs within the 1q32 locus from our GWAS analysis and the Gharavi et al study rs3766404(c*) rs6677604(a*) study Yu et al cohort Discovery (Southern Chinese) sample size MAF MAF OR P OR P (case/control) (Cases/Controls) (Cases/Controls) 1434/4270 0.073/0.075 0.98 8.35E-01 0.050/0.055 0.94 5.21E-01 Gharavi et al Discovery (Beijing) 1194/902 0.052/0.086 0.59 1.84E-05 0.041/0.073 0.55 1.20E-05 Replication (Shanghai) 712/748 0.078/0.08 0.98 8.18E-01 0.052/0.07 0.73 3.22E-02 Replication (European ) 1238/1172 0.12/0.14 0.82 1.46E-02 0.17/0.23 0.71 1.19E-05 * Minor allele 13

Supplementary table 10 Clinical characteristics of the IgAN Patients of the GWAS and replication cohorts Sample GWAS Replication study 1 Replication study 2 Total northern China cohort southern China cohort Estimated GFR(ml/min/1.73m 2 ) (mean) 90.7 93.3 89.7 90.5 CKD stage 1(%) 51.40% (580) 49.00% (101) 47.80% (502) 42.29% (1183) CKD stage 2(%) 23.60% (267) 20.90% (43) 27.30% (287) 25.50% (612) CKD stage 3(%) 14.80% (167) 18.40% (38) 17.90% (188) 16.38% (393) CKD stage 4(%) 5.60% (63) 5.80% (12) 4.30% (45) 5.00% (120) CKD stage 5(%) 4.60% (52) 5.80% (12) 2.70% (28) 3.83% (92) Serum IgA level (mg/ml) (mean) 3.4 3.0 2.8 3.1 Proteinuria (g/day) (no.) 1081 156 1034 2271 <0.3 (%) 23.96% (259) 5.77% (9) 12.19% (126) 17.35% (394) 0.3 & <1(%) 41.91% (453) 33.33% (52) 36.65% (379) 38.93% (884) 1 & <3(%) 25.44% (275) 40.38% (63) 33.17% (343) 29.99% (681) 3(%) 8.70% (94) 20.51% (32) 17.99% (186) 13.74% (312) Microhematuria (RBC/hp) (no.) 723 77 226 1026 <3 (%) 60.44% (437) 19.48% (15) 13.72% (31) 47.08% (483) 3 & <10 (%) 15.35% (111) 44.16% (34) 20.35% (46) 18.62% (191) 10& <100 (%) 14.25% (103) 25.97% (20) 32.74% (74) 12.38% (127) 100 (%) 9.96% (72) 10.39% (8) 33.19% (75) 15.11% (155) Clinical subtypes of IgAN (no.) 566 212 1184 1962 asymptomatic hematuria or proteinuria (%) 22.79% (129) 23.11% (49) 34.04% (403) 29.61% (581) nephritic syndrome(%) 73.14% (414) 64.62% (137) 52.45% (621) 59.73% (1172) nephrotic syndrome(%) 4.07% (23) 12.27% (26) 13.51% (160) 10.65% (209) 14

Lee's Grade (no.) 870 105 975 Grade (%) 2.29% (20) 14.29% (15) 3.59% (35) Grade (%) 9.20% (80) 20.95% (22) 10.46% (102) Grade (%) 60.11% (523) 57.14% (60) 59.79% (583) Grade (%) 18.97% (165) 4.76% (5) 17.44% (170) Grade (%) 9.43% (82) 2.86% (3) 8.71% (85) 15

Supplementary Table 11 Association of the top 7 SNPs with clinical phenotype in IgAN patients* clinical subtype a log(proteinuria) b log(iga level) c log(gfr) d CHR SNP MA* OR 95% CI P BETA 95% CI P BETA 95% CI P BETA 95% CI P 8 rs2738048 G 1.088 0.951 1.246 0.220 0.026-0.038 0.089 0.431-0.002-0.025 0.020 0.848-0.001-0.048 0.047 0.983 17 rs3803800 A 1.017 0.891 1.159 0.806-0.035-0.095 0.025 0.252 0.026 0.005 0.047 0.014 0.015-0.030 0.060 0.523 17 rs4227 G 1.029 0.889 1.191 0.703-0.015-0.082 0.052 0.667 0.014-0.009 0.038 0.226 0.010-0.039 0.059 0.697 22 rs12537 T 1.028 0.865 1.221 0.754 0.121 0.044 0.198 0.002-0.022-0.048 0.005 0.117 0.000-0.059 0.060 0.987 6 rs2523946 T 1.064 0.940 1.204 0.330 0.025-0.032 0.082 0.391 0.014-0.006 0.034 0.173-0.047-0.089-0.004 0.031 6 rs660895 G 0.818 0.716 0.936 0.003-0.071-0.133-0.009 0.025 0.022 0.000 0.044 0.047 0.009-0.037 0.055 0.696 6 rs1794275 A 0.884 0.762 1.025 0.102-0.013-0.082 0.055 0.704 0.015-0.009 0.039 0.213 0.047-0.004 0.099 0.073 *Linear regression was applied for the correlation analysis of natural log-transformed serum IgA level, natural log-transformed proteinuria and natural log-transformed egfr Binary logistic regression was carried out for the correlation analysis of history of gross hematuria Ordinal logistic regression was performed for the correlation analysis of clinical subtype, microscopic hematuria, CKD stage at the time of biopsy, and Lee s biopsy grade a clinical subtype: asymptomatic hematuria or proteinuria (urine protein <3.5g/24h, Scr<1.3mg/dl and without edema or hypertension); nephritic syndrome (urine protein<3.5g/24h, with or without Scr>1.3mg/dl, or edema, or hypertension); nephrotic syndrome (urine protein 3.5g/24h) b 24-hour proteinuria level: none/mild (<0.3 gm/day), moderate (0.3-1 gm/day), (1-3gm/day), severe (>3 gm/day) c natural log-transformed serum IgA level (mg/ml) at the time of kidney biopsy d egfr (estimated glomerular filtration rate using the MDRD formula) 16

Supplementary Table 11 Correlation of the top 7 SNPs with clinical phenotype in IgAN patients (continued) gross hematuria e microscopic hematuria f CKD stage g Lee's grade h CHR SNP MA* OR 95% CI P OR 95% CI P OR 95% CI P OR 95% CI P 8 rs2738048 G 1.067 0.951 1.197 0.268 0.989 0.829 1.180 0.904 1.004 0.892 1.130 0.951 0.874 0.716 1.067 0.186 17 rs3803800 A 0.933 0.838 1.039 0.206 0.973 0.824 1.149 0.751 0.928 0.830 1.038 0.192 1.075 0.892 1.295 0.449 17 rs4227 G 0.886 0.785 1.001 0.052 1.019 0.853 1.217 0.835 0.914 0.808 1.034 0.153 1.129 0.926 1.377 0.230 22 rs12537 T 0.966 0.841 1.110 0.628 1.109 0.887 1.388 0.364 0.909 0.783 1.056 0.211 1.049 0.820 1.343 0.703 6 rs2523946 T 1.127 1.017 1.249 0.022 0.997 0.852 1.168 0.975 1.056 0.951 1.173 0.307 1.094 0.919 1.302 0.314 6 rs660895 G 0.982 0.879 1.098 0.750 1.108 0.940 1.305 0.221 0.964 0.861 1.079 0.521 1.091 0.910 1.308 0.348 6 rs1794275 A 1.080 0.956 1.221 0.216 1.156 0.954 1.399 0.139 0.944 0.831 1.073 0.379 1.067 0.859 1.325 0.559 *Linear regression was applied for the correlation analysis of natural log-transformed serum IgA level, natural log-transformed proteinuria and natural log-transformed egfr Binary logistic regression was carried out for the correlation analysis of history of gross hematuria Ordinal logistic regression was performed for the correlation analysis of clinical subtype, microscopic hematuria, CKD stage at the time of biopsy, and Lee s biopsy grade e. gross hematuria defined by clinical history, present/absent, logistic regression model f. microhematuria: grade 0 (<3 RBC/hpf), grade 1 (3-10 RBC/hpf), grade 2 (10-100 RBC/hpf), grade 3 (>100 RBCs/hpf) g. CKD stage: stage 1 (GFR 90 ml/min), stage 2 (GFR:60-89 ml/min), stage 3 (GFR:30-59 ml/min), stage 4 (GFR:15-29ml/min), stage 5 (GFR<15 ml/min) h. kidney biopsy Lee classification, grade 1-5 17

Supplementary Table 12 Means of serum IgA level, GFR and proteinuria in the IgAN patients carrying the different genotypes of rs3803800, rs2523946 and rs12537 rs3803800 Genotype GG GA AA Mean of IgA level(mg/ml) (95% CI) 2.92 (2.85-3.00) 2.97 (2.90-3.04) 3.10 (2.99-3.21) No of Observations 1131 1459 433 rs2523946 Genotype CC CT TT Mean of GFR (ml/min/1.73m 2 ) (95%CI) 91.72 (88.53-94.92) 91.87 (88.99-94.76) 88.56 (84.40-92.73) No of Observations 760 1123 490 rs12537 Genotype CC CT TT Mean of Proteinuria (g/day) (95% CI) 1.53 (1.45-1.62) 1.64 (1.50-1.79) 1.94 (1.46-2.43) No of Observations 2112 775 91 18

Supplementary Table 13 The allele frequencies of the 7 validated SNPs in selected HapMap reference populations allele frequency SNP CHR POSITION LOCUS Allele CHB JPT CEU YRI rs2738048 8 6810195 DEFA G 0.30 0.42 0.29 0.18 rs3803800 17 7403693 TNFSF13 A 0.31 0.29 0.22 0.78 rs4227 17 7431901 MPDU1 G 0.20 0.15 0.25 0.54 rs12537 22 28753460 MTMR3 T 0.25 0.16 0.31 0.47 rs2523946 6 30049922 HLA-A T 0.50 0.46 0.48 0.48 rs660895 6 32685358 HLA-DRB1 G 0.20 0.30 0.28 0.10 rs1794275 6 32779226 HLA-DQA/B A 0.19 0.25 0.20 0.23 * Allelic frequency information based on HapMap Data Release 28 (phase II+III); only founder genotypes included in the analysis. Population descriptors: JPT: Japanese in Tokyo, Japan (N=45). CHB: Han Chinese in Beijing, China (N=45). CEU: Utah residents with Northern and Western European ancestry from the CEPH collection (N=60). YRI: Yoruban in Ibadan, Nigeria (N=60). 19

Supplementary Figure 1 Principal component analysis (PCA) of the discovery sample A-B: Plots of the first three PCs, which were derived from the PCA analysis of 5704 subjects of the discovery sample and 194 HapMap samples. All the cases are labeled in red, whereas the controls were labeled in white (Guangdong), green (northern Chinese) and purple (Singapore Chinese). The HapMap samples are labeled in blue (CHB), incarnadine (JPT), yellow (CEU) and orange (YRI). C-F: Plots between the 1 st and the 2 nd -5 th PCs, which derived from the PCA analysis of 1434 IgAN patients and 4270 controls (971 Guangdong controls, 2071 Singapore controls and 1228 northern Chinese controls). All the cases are in red, and the controls are labeled in yellow (Guangdong), blue (northern Chinese) and white (Singaporean Chinese). G-J: Plots between the 1 st and the 2 nd -5 th PCs from the PCA analysis using the three genetically homogeneous clusters of 1434 IgAN cases and 4270 controls determined by the Kmeans method. The samples are labeled in red (cluster 1), yellow (cluster 2) and blue (cluster 3). 20

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Supplementary Figure 2 The Quantile-Quantile (QQ) plot of the observed P values from the genome-wide association analysis of the discovery sample. The plot in red is for the P values from all the 444,882 SNPs, whereas the plot in blue is for the P values after excluding the 2644 SNPs within the MHC region (chr. 6:28-34 Mb). (A) QQ plot of observed P values of association from the analysis in 1434 IgAN patients and 4270 controls with PCA-based correction for population stratification. GC calculated is 1.058 with all the SNPs or 1.054 after excluding the 2,644 SNPs within the MHC region. (B) QQ plot of the observed P values from the association analysis in 1434 IgAN patients and 4270 controls by using three genetically homogeneous clusters. GC is 1.079 with all the SNPs or 1.074 after excluding the 2644 SNPs within the MHC region. 22

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Supplementary figure 3 Regional plots of the association results from the discovery sample and the recombination rate within the MHC region. Association was assessed using logistic regression analysis with adjustment for the top five PCs of the population stratification (panel A) and forward stepwise conditional analysis on rs2523946, rs9264942, rs1794275, rs660895 and rs9277554 (panel B). The log 10 P values of the SNPs (y axis) are presented as open triangles against their chromosomal positions (x axis). The top SNP within the region is indicated by a blue triangle. The recombination rate (cm/mb) (Build 35 and estimated by using the HapMap CHB+JPT samples) was presented in blue lines, and the genes within the region are shown as green arrows. 24

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Supplementary figure 4 Regional plot of the association results from the discovery sample within the 22q12.2 locus. The log 10 P values of the SNPs (y axis) are presented as open triangles against their chromosomal positions (x axis). The top SNP within the region, rs12537 is indicated by a blue triangle, and its LD (r 2 ) values with the rest of SNPs were indicated by different gradient of red colors. The previously reported SNPs rs2412971 and rs2412973 are labeled in the plot. The recombination rate (cm/mb) (Build 35 and estimated by using the HapMap CHB+JPT samples) was presented in blue lines, and the genes within the region are shown as green arrows. 26

Supplementary figure 5 Regional association plot of the association results from the discovery sample within the 1q32 locus. The log 10 P (y axis) values of both genotyped (triangles) and imputed (circles) SNPs are presented against their chromosomal positions (x axis). The reported SNP rs6677604 within the region is indicated by a blue triangle, and its LD (r 2 ) values with the rest of SNPs were indicated by different gradient of red colors. The top imputed SNP rs12059767 within suggestive association on the left side of the 1q32 locus is indicated by a blue enclosed circle, and its LD (r 2 ) values with the surrounding SNPs were indicated by different gradient of red colors. The recombination rate (cm/mb) (Build 35 and estimated by using the HapMap CHB+JPT samples) was presented in light blue lines, and the genes within the region are shown as green arrows. 27

Supplementary figure 6 The results of the Fst, ihs and XP-EHH for the two novel loci (A. 8P23.1; B. 17P13) using the HGDP Selection Browser from the Pritchard Lab (http://hgdp.uchicago.edu/cgi-bin/gbrowse/hgdp/). Fst: The position of a SNP in the worldwide FST distribution. Values are log (10) of the fraction of SNPs with a more extreme value than the SNP in question; ihs Continent: ihs, as calculated in Voight et al. (2006). Presented is the -log10 of the empirical p-value for a window of 30 SNPs; XP-EHH Continent: XP-EHH, calculated as in Sabeti et al. (2007). A: 8p23.1 (6710-6910 Kb) B 17p13 7200-7600Kb 28

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