a large-scale screen for coding variants predisposing to ... · a large-scale screen for coding...

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Supplementary Information

A large-scale screen for coding variants predisposing to psoriasis

Huayang Tang, Xin Jin, Yang Li, Hui Jiang, Xianfa Tang, Xu Yang, Hui Cheng, Ying

Qiu, Gang Chen, Junpu Mei, Fusheng Zhou, Renhua Wu, Xianbo Zuo, Yong Zhang,

Xiaodong Zheng, Qi Cai, Xianyong Yin, Cheng Quan, Haojing Shao, Yong Cui,

Fangzhen Tian, Xia Zhao, Hong Liu, Fengli Xiao, Fengping Xu, Jianwen Han,

Dongmei Shi, Anping Zhang, Cheng Zhou, Qibin Li, Xing Fan, Liya Lin, Hongqing

Tian, Zaixing Wang, Huiling Fu, Fang Wang, Baoqi Yang, Shaowei Huang, Bo Liang,

Xuefeng Xie, Yunqing Ren, Qingquan Gu, Guangdong Wen, Yulin Sun, Xueli Wu,

Lin Dang, Min Xia, Junjun Shan, Tianhang Li, Lin Yang, Xiuyun Zhang, Yuzhen Li10,

Chundi He, Aie Xu, Liping Wei, Xiaohang Zhao, Xinghua Gao, Jinhua Xu, Furen

Zhang, Jianzhong Zhang, Yingrui Li, Liangdan Sun, Jianjun Liu, Runsheng Chen, Sen

Yang, Jun Wang & Xuejun Zhang

Nature Genetics: doi:10.1038/ng.2827

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Table of Contents Supplementary Tables

Supplementary Table 1. The summary of samples analyzed in this study…………………………………………………………….………………..4 Supplementary Table 2. Data production summary……………………………...5 Supplementary Table 3. SNVs detected in exome sequencing and targeted sequencing………………………………………………………….…………….6 Supplementary Table 4.

(a) Single-nucleotide variant transition:transversion ratio on different level of exome sequencing data……………………………………………………7

(b) Single-nucleotide variant transition:transversion ratio on different level of target sequencing data……………………………………………………..7

Supplementary Table 5. (a) Distribution of SNVs with different MAF of exome sequencing

data………………………………………………………………………...8 (b) Distribution of SNVs with different MAF of target sequencing

data……………………………………………………………………….8 Supplementary Table 6. Top 133 nonsynonymous SNVs in exome sequencing...9 Supplementary Table 7. 742 genes by gene-based analysis from exome sequencing and targeted sequencing data ………………..…...………………..15 Supplementary Table 8. Targeted sequencing of 565 immune related genes (not included psoriasis GWAS loci) and results of gene-based test…………………15 Supplementary Table 9. Targeted sequencing of 57 genes in psoriasis GWAS loci and results of gene-based test ………………...…………………………...15 Supplementary Table 10. Genotype concordance between targeted sequencing and genotyping by Sequenom…………………………………..........................16 Supplementary Table 11. Common and low frequency nonsynonymous SNVs with P < 0.01 in targeted sequencing…………………………………………...17 Supplementary Table 12. Association results of 2 rare variants by condition on the common variant in FUT2…………………………………………………...20 Supplementary Table 13.

(a) Replication results of known nonsynonymous SNVs in this study………21 (b) Further validation of rs11652075 within CARD14 by genotyping in

additional 4,480 cases and 6,521 controls…………………………..……21 Supplementary Table 14. Haplotype analysis between GWAS SNPs and missense SNVs…………………………………………………………………………....22 Supplementary Table 15. Further haplotype analysis in GJB2….……….……..24 Supplementary Table 16. Replication of 133 nonsynonymous SNVs by targeted sequencing………………………………………………………………………25 Supplementary Table 17. Gene-based analysis for IL23R and GJB2….…….….31 Supplementary Table 18. Depth and coverage per gene….……….…….……...32 Supplementary Table 19. Recovery rate of SNPs in 1000 Genomes Project Han Chinese population ……………………………………………………………...32


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Supplementary Figures Supplementary Figure 1. Description of the study design…….…………..……33 Supplementary Figure 2. Depth distribution of sequencing…….………………34 Supplementary Figure 3. Manhattan plot of nonsynonymous SNVs in exome sequencing………………………………………………………………………35 Supplementary Figure 4. Manhattan plot of nonsynonymous SNVs in targeted sequencing………………………………………………………………………35 Supplementary Figure 5. Structure of the connexin 26 gap junction channel (GJB2) at 3.5 A resolution…………………..…………………………………………………..36 Supplementary Figure 6. Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) …………………………………………………….36 Supplementary Figure 7. Power calculator in combined samples 10,727 cases and 10,582 controls……………………………………………………………..37 Supplementary Figure 8. PCA analysis in exome sequencing and targeted sequencing………………………………………………………………………38


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Supplementary Table 1. The summary of samples analyzed in this study

Exom sequencing Targeted sequencing

Cases Controls Cases Controls Samples size 781 676 9,946 9,906 Mean age (s.d.) 30.92 (12.47) 34.12 (12.92) 35.15 (14.49) 35.81 (16.01) Mean age of onset (s.d.) 22.45 (9.39) 27.02 (13.47) Male/female 458/323 407/269 5,864/4,082 5,329/4,577


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Supplementary Table 2. Data production summary Exome sequencing Targeted seuqencing

Cases Controls Total Cases Controls Total

# of individuals 800 700 1,500 10,003 10,002 20,005 Raw basesa (Gb) 2.16±0.61 2.42±0.63 2.28±0.64 1.10±0.22 1.18±0.27 1.14±0.25 Mapped basesa (Gb) 1.81±0.53 2.07±0.55 1.93±0.56 1.08±0.22 1.16±0.27 1.12±0.25 Mapped bases on targetsa (Gb) 1.03±0.42 1.18±0.40 1.10±0.42 0.60±0.12 0.63±0.14 0.62±0.13 Capture specificitya(%) 68.49±8.11 69.87±3.47 69.13±6.42 64.56±5.32 64.13±6.94 64.34±6.21 Average sequencing depthb (fold) 28.62±9.39 33.34±9.11 30.82±9.55 63.73±12.86 67.16±15.35 65.45±14.26 Fraction of target covered >= 1X(%) 98.94±0.63 99.07±0.54 99.00±0.59 99.48±0.25 99.51±0.24 99.50±0.25 Fraction of target covered >= 4X(%) 96.28±2.80 97.07±2.44 96.65±2.67 98.77±0.88 98.83±0.87 98.80±0.88 Fraction of target covered >= 8X(%) 90.68±7.19 93.23±5.99 91.87±6.78 97.43±1.51 97.57±1.53 97.50±1.52 Fraction of target covered >= 16X(%) 73.55±15.86 80.88±12.02 76.97±14.66 92.39±3.20 92.87±3.24 92.63±3.23 a all sequencing reads were included. b read duplicates were removed.


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Supplementary Table 3. SNVs detected in exome sequencing and targeted sequencing

Function Exome sequencing Target sequencing

MAF < 1% MAF< 5% All MAF < 1% MAF< 5% All

synonymous 51,740 57,658 71,438 44,064 44,725 45,350 stopgain 1,868 1,947 2,090 2,314 2,331 2,337 stoploss 102 111 133 55 56 57 splicing 904 976 1,057 1,378 1,384 1,390

nonsynonymous 87,555 94,305 106,868 78,682 79,376 79,993 UTR5 7,720 8,962 11,672 7,725 7,818 7,935 UTR3 13,037 15,276 20,326 16,681 16,878 17,168

UTR5;UTR3 96 103 144 92 92 95 intronic 192,008 225,548 304,580 265,008 268,308 274,150

Sum 355,030 404,886 518,308 415,999 420,968 428,475


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Supplementary Table 4

(a) Single-nucleotide variant transition: transversion ratio on different level of exome sequencing data

# of mutate samples

SNV Ti/Tv

1 all 2.223 1 novel 2.211 2 all 2.203 2 novel 2.174

3-8 all 2.356 3-8 novel 2.305 >8 all 2.485 >8 novel 2.217

Mean all 2.32

(b) Single-nucleotide variant transition: transversion ratio on different level of target sequencing data

# of mutate samples

SNV Ti/Tv

1 all 1.902 1 novel 1.900 2 all 2.280 2 novel 2.274

3-100 all 2.652 3-100 novel 2.651 >100 all 2.124 >100 novel 1.870 Mean all 2.50


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Supplementary Table 5 (a) Distribution of SNVs with different MAF of exome sequencing data

MAF #of SNVs Proportion

Singleton 203,596 37.15% Doubleton 55,436 10.12% (0,0.005) 346,322 63.20%

[0.005,0.01) 27,003 4.93% [0.01,0.05) 53,274 9.72% [0.05,0.1) 25,295 4.62% [0.1,0.2) 31,881 5.82% [0.2,0.3) 22,996 4.20% [0.3,0.4) 20,755 3.79% [0.4,0.5] 20,452 3.73%

All 547,978 100.00%

(b) Distribution of SNVs with different MAF of target sequencing data

MAF #of SNVs Proportion

Singleton 61,193 13.44% Doubleton 40,453 8.88% (0,0.005) 439,080 96.43%

[0.005,0.01) 2,894 0.64% [0.01,0.05) 5,296 1.16% [0.05,0.1) 1,934 0.42% [0.1,0.2) 2,296 0.50% [0.2,0.3) 1,430 0.31% [0.3,0.4) 1,273 0.28% [0.4,0.5] 1,111 0.24%

All 455,314 100.00%


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Supplementary Table 6. Top 133 nonsynonymous SNVs in exome sequencing

CHR SNP BP (hg18) Allele F_A F_U P OR

Sample

covered HWE Function Genes

1 chr1_1445449 1445449 T/C 0.0184 0.005988 3.00E-03 3.111 0.98 1.00E+00 nonsynonymous ATAD3A

1 rs12036962 3797118 C/G 0.1686 0.1376 2.14E-02 1.27 0.99 5.14E-01 nonsynonymous C1orf174

1 rs10909820 3797310 A/C 0.1727 0.1389 1.27E-02 1.293 1.00 6.29E-01 nonsynonymous C1orf174

1 rs5746026 12175649 A/G 0.02881 0.04889 4.77E-03 0.5771 1.00 1.00E+00 nonsynonymous TNFRSF1B

1 chr1_22182802 22182802 T/C 0.02196 0.04315 1.20E-03 0.4979 0.99 6.28E-01 nonsynonymous ELA3B

1 rs3795424 32933231 G/T 0.1357 0.1071 1.96E-02 1.308 0.99 8.41E-01 nonsynonymous SYNC

1 chr1_36527627 36527627 G/C 0.0186 0.0347 8.26E-03 0.53 0.96 1.00E+00 nonsynonymous THRAP3

1 chr1_52596134 52596134 G/C 0.0254 0.03858 4.59E-02 0.6495 0.97 6.17E-01 nonsynonymous CC2D1B

1 rs2495477 55291055 G/A 0.2916 0.2410 2.36E-03 1.30 0.98 9.16E-01 nonsynonymous PCSK9

1 rs17117720 58777205 A/G 0.1384 0.1039 5.41E-03 1.384 0.97 1.00E+00 nonsynonymous OMA1

1 chr1_67421184 67421184 A/G 0.0296 0.0580 1.62E-04 0.50 1.00 7.19E-01 nonsynonymous IL23R

1 chr1_91515129 91515129 T/C 0.008535 0.01932 1.60E-02 0.437 0.93 1.00E+00 nonsynonymous HFM1

1 rs45455292 111759093 C/G 0.0014 0.0109 1.11E-03 0.13 0.95 1.79E-03 nonsynonymous OVGP1

1 rs2798901 143590621 A/G 0.06364 0.08974 8.43E-03 0.6893 0.98 6.59E-03 nonsynonymous PDE4DIP

1 rs2275249 145225944 G/C 0.1562 0.2132 8.28E-05 0.68 0.99 7.29E-01 nonsynonymous CHD1L

1 chr1_151000000 151000000 G/C 0.0448 0.0715 2.06E-03 0.61 0.99 1.00E+00 nonsynonymous KPRP

1 rs753856 159762758 G/C 0.1459 0.1907 1.94E-03 0.72 0.94 1.00E+00 nonsynonymous HSPA6

1 rs2272792 165096146 T/C 0.1242 0.1567 1.24E-02 0.7629 0.98 7.71E-01 nonsynonymous TADA1L

1 rs6692219 178256207 C/G 0.03057 0.05068 6.82E-03 0.5907 0.96 4.03E-01 nonsynonymous CEP350

1 rs2295950 183442460 C/A 0.09956 0.07031 7.24E-03 1.462 0.90 7.61E-01 nonsynonymous C1orf26

1 rs12139527 199275805 G/A 0.1205 0.09657 4.86E-02 1.282 0.90 7.15E-02 nonsynonymous CACNA1S


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1 rs2275866 199618044 A/T 0.08601 0.06018 8.03E-03 1.47 1.00 5.03E-01 nonsynonymous LAD1

1 chr1_239824570 239824570 T/C 0.01102 0.02229 1.70E-02 0.489 0.99 1.00E+00 nonsynonymous OPN3

2 rs1879761 26604273 A/G 0.2042 0.2492 4.55E-03 0.77 0.97 2.99E-01 nonsynonymous OTOF

2 rs1881421 29269870 G/C 0.2737 0.2259 4.01E-03 1.29 0.96 3.11E-01 nonsynonymous ALK

2 rs1881420 29269985 T/C 0.2722 0.2247 3.82E-03 1.29 0.97 7.36E-01 nonsynonymous ALK

2 chr2_152027704 152027704 A/G 0.0121 0.0276 4.39E-03 0.43 0.92 3.82E-01 nonsynonymous RIF1

2 rs2123465 152028364 G/A 0.2293 0.1873 8.33E-03 1.29 0.92 2.99E-01 nonsynonymous RIF1

2 rs3762568 207339706 A/G 0.0169 0.0321 8.54E-03 0.52 0.97 1.00E+00 nonsynonymous FASTKD2

2 rs17235409 218967976 A/G 0.1194 0.1546 7.53E-03 0.74 0.95 8.80E-01 nonsynonymous SLC11A1

2 rs1035834 230569763 T/G 0.1376 0.0971 9.77E-04 1.48 0.96 1.00E+00 nonsynonymous FBXO36

2 chr2_239726340 239726340 T/C 0.0613 0.0355 1.37E-03 1.77 1.00 1.00E+00 nonsynonymous HDAC4

2 chr2_240714874 240714874 T/C 0.0769 0.1078 4.21E-03 0.69 0.98 1.04E-01 nonsynonymous MYEOV2

2 rs757978 242019774 T/C 0.0207 0.009731 1.79E-02 2.151 0.99 1.00E+00 nonsynonymous FARP2

3 rs455863 9931279 A/G 0.05039 0.07357 9.88E-03 0.6682 0.98 5.68E-01 nonsynonymous IL17RE

3 rs708567 9935070 T/C 0.0512 0.0752 8.04E-03 0.66 0.99 5.73E-01 nonsynonymous IL17RC

3 rs34833812 30688623 T/C 0.01609 0.02967 1.36E-02 0.5347 1.00 1.00E+00 nonsynonymous TGFBR2

3 rs35217513 40532447 A/C 0.1101 0.1461 5.62E-03 0.7234 0.91 8.15E-02 nonsynonymous ZNF620

3 chr3_65413949 65413949 T/C 0.007802 0.01704 2.36E-02 0.4537 0.99 1.00E+00 nonsynonymous MAGI1

3 rs41272317 133820167 A/C 0.06525 0.08912 1.81E-02 0.7134 0.95 1.30E-02 nonsynonymous ACAD11

4 rs34860182 6976138 G/C 0.03718 0.02112 1.19E-02 1.79 0.97 1.00E+00 nonsynonymous TBC1D14

4 rs10007352 10056777 T/C 0.1086 0.1413 7.96E-03 0.7405 0.99 2.63E-01 nonsynonymous ZNF518B

4 rs17013285 88986032 A/G 0.2324 0.2804 4.27E-03 0.78 0.94 3.79E-01 nonsynonymous MEPE

4 chr4_187390284 187390284 T/C 0.0248 0.0097 2.35E-03 2.59 0.99 1.00E+00 nonsynonymous KLKB1

5 rs10941112 34040464 T/C 0.3130 0.3623 5.13E-03 0.80 1.00 8.02E-01 nonsynonymous AMACR


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5 rs10805625 37211848 G/A 0.0546 0.0292 8.53E-04 1.92 0.98 4.36E-01 nonsynonymous C5orf42

5 chr5_55515162 55515162 G/C 0.01605 0.006667 1.89E-02 2.43 1.00 1.00E+00 nonsynonymous ANKRD55

5 rs2240696 140148254 A/G 0.3995 0.4448 1.42E-02 0.8304 0.99 6.39E-01 nonsynonymous PCDHA1

5 rs2240695 140148335 G/T 0.4041 0.4428 3.74E-02 0.8534 0.97 6.38E-01 nonsynonymous PCDHA1

5 rs11167600 140155049 G/C 0.3982 0.4422 1.76E-02 0.8344 0.97 8.13E-01 nonsynonymous PCDHA2

5 rs4141841 140183616 C/T 0.4067 0.4472 3.32E-02 0.8475 0.93 8.11E-01 nonsynonymous PCDHA5

5 rs17844301 140189068 C/A 0.0393 0.02003 2.54E-03 2.002 1.00 2.33E-01 nonsynonymous PCDHA6

5 rs17844323 140208597 A/C 0.0783 0.1085 7.20E-03 0.70 0.93 6.83E-01 nonsynonymous PCDHA9

5 rs11435 145422326 A/G 0.2950 0.2500 7.08E-03 1.26 0.99 5.35E-01 nonsynonymous SH3RF2

5 rs4958531 151752031 C/T 0.05641 0.03476 5.59E-03 1.66 1.00 1.00E+00 nonsynonymous NMUR2

5 rs4958532 151752045 A/G 0.05584 0.03481 6.99E-03 1.64 1.00 1.00E+00 nonsynonymous NMUR2

5 rs1895245 151752248 T/G 0.05746 0.03518 5.04E-03 1.672 0.98 1.00E+00 nonsynonymous NMUR2

5 rs4958535 151755257 G/C 0.0570 0.0348 4.71E-03 1.68 1.00 1.00E+00 nonsynonymous NMUR2

6 rs2395617 35393698 A/C 0.0329 0.0141 1.00E-03 2.38 1.00 1.00E+00 nonsynonymous DEF6

6 chr6_47085808 47085808 T/A 0.01015 0.02184 1.28E-02 0.4593 0.96 1.00E+00 nonsynonymous GPR110

6 rs1932618 69723405 A/G 0.1365 0.1052 9.96E-03 1.35 1.00 1.51E-01 nonsynonymous BAI3

6 rs3747787 107074471 C/T 0.1121 0.08157 6.52E-03 1.421 0.97 7.93E-01 nonsynonymous AIM1


6 chr6_138680135 138680135 G/A 0.03282 0.01929 2.37E-02 1.725 1.00 1.00E+00 nonsynonymous KIAA1244

6 rs73606794 150039036 A/C 0.02553 0.01374 2.76E-02 1.881 0.93 1.12E-01 stoploss LATS1

6 rs56149740 150047208 T/G 0.0263 0.0121 6.74E-03 2.21 0.97 1.00E+00 nonsynonymous LATS1

6 rs2027063 169886153 A/C 0.0213 0.0437 9.16E-04 0.48 0.95 3.50E-01 nonsynonymous TCTE3

7 chr7_2549433 2549433 T/C 0.2547 0.3025 5.02E-03 0.7883 0.95 9.26E-01 nonsynonymous C7orf27



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7 chr7_34052446 34052446 A/G 0.1100 0.0750 1.26E-03 1.52 1.00 2.56E-01 nonsynonymous BMPER

7 chr7_133582908 133582908 T/C 0.0205 0.0082 6.10E-03 2.54 1.00 1.00E+00 nonsynonymous LRGUK

7 rs2290971 148343025 A/G 0.0885 0.0615 6.15E-03 1.48 1.00 5.04E-01 nonsynonymous PDIA4

7 rs1130496 157652656 T/C 0.3502 0.4067 2.91E-03 0.79 0.91 1.04E-02 nonsynonymous PTPRN2

8 chr8_11740062 11740062 G/T 0.04793 0.03055 1.73E-02 1.597 0.99 1.00E+00 nonsynonymous CTSB

8 rs1801280 18302134 C/T 0.04127 0.022 4.07E-03 1.913 0.95 1.00E+00 nonsynonymous NAT2

8 chr8_22035968 22035968 A/C 0.0104 0.0231 7.32E-03 0.44 1.00 2.98E-01 nonsynonymous HR

8 chr8_69162517 69162517 T/G 0.09493 0.1265 6.83E-03 0.7243 0.99 6.03E-01 nonsynonymous PREX2

8 rs920829 73140257 T/C 0.2889 0.3356 7.20E-03 0.8045 0.98 4.35E-01 nonsynonymous TRPA1

9 rs3814541 108729573 T/C 0.1041 0.07746 1.67E-02 1.384 0.92 5.74E-01 nonsynonymous ZNF462

9 rs1801968 131620722 G/C 0.07403 0.1057 2.89E-03 0.6767 0.99 6.75E-02 nonsynonymous TOR1A

10 chr10_13257566 13257566 G/C 0.006631 0.01584 1.87E-02 0.4148 0.97 1.00E+00 nonsynonymous MCM10

10 rs3750575 74808697 T/C 0.0608 0.0378 4.62E-03 1.65 1.00 6.18E-01 nonsynonymous ANXA7

10 rs11556392 99429546 C/A 0.058 0.04111 3.93E-02 1.436 0.97 6.21E-01 nonsynonymous AVPI1

10 chr10_105787507 105787507 C/A 0.01147 0.02187 3.02E-02 0.519 0.96 1.00E+00 nonsynonymous COL17A1

10 chr10_108449102 108449102 T/C 0.0084 0.0208 4.60E-03 0.40 1.00 1.00E+00 nonsynonymous SORCS1

10 chr10_115937861 115937861 A/G 0.03079 0.01366 2.37E-03 2.294 0.97 1.00E+00 nonsynonymous TDRD1

11 rs2061586 548884 C/T 0.1459 0.184 8.03E-03 0.7579 0.92 4.28E-01 nonsynonymous C11orf35

11 rs10768450 4977408 T/C 0.06818 0.09552 7.28E-03 0.6928 0.99 8.23E-01 nonsynonymous OR51L1

11 rs1965207 6869819 C/T 0.02956 0.04545 2.37E-02 0.6397 0.99 3.90E-01 nonsynonymous OR2D2

11 rs1453547 58946488 A/G 0.154 0.1222 1.38E-02 1.307 0.99 1.50E-01 nonsynonymous OR5A2

11 chr11_64577311 64577311 T/C 0.01556 0.02819 1.94E-02 0.545 0.99 1.00E+00 nonsynonymous NAALADL1

11 rs61902276 82303462 A/G 0.05821 0.08309 8.81E-03 0.6822 0.99 6.11E-01 nonsynonymous C11orf82

11 rs17099008 101987714 G/T 0.1214 0.09023 7.18E-03 1.393 0.98 2.32E-01 nonsynonymous MMP20


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11 rs2305830 116771522 G/C 0.2307 0.2736 8.50E-03 0.80 0.98 4.92E-01 nonsynonymous CEP164

11 chr11_123391517 123391517 T/C 0.1732 0.209 1.45E-02 0.7928 0.99 9.73E-03 nonsynonymous OR10G4

12 rs1045546 6438168 T/C 0.0212 0.0075 2.32E-03 2.88 1.00 1.00E+00 nonsynonymous TAPBPL

12 rs10849482 6505535 A/G 0.02083 0.007485 2.96E-03 2.821 0.99 1.00E+00 nonsynonymous NCAPD2

12 chr12_45757822 45757822 G/C 0.03721 0.02174 1.61E-02 1.739 0.97 1.00E+00 nonsynonymous AMIGO2

12 rs2232405 51108409 G/A 0.09763 0.07303 1.93E-02 1.373 0.98 1.00E+00 nonsynonymous KRT75

12 rs2232387 51113875 T/C 0.1059 0.0730 2.38E-03 1.51 0.98 5.66E-01 nonsynonymous KRT75

12 rs925368 108875362 C/T 0.06795 0.09138 1.94E-02 0.7249 1.00 1.00E+00 nonsynonymous GIT2

12 rs3741466 115949647 T/C 0.1128 0.08519 1.32E-02 1.366 1.00 1.00E+00 nonsynonymous FBXW8

13 rs72474224 19661612 T/C 0.0795 0.0520 3.08E-03 1.57 1.00 6.99E-01 nonsynonymous GJB2

13 rs61729904 51263355 T/G 0.04155 0.02652 2.97E-02 1.592 0.96 1.00E+00 nonsynonymous DHRS12

13 chr13_87127473 87127473 A/T 0.025 0.01263 1.56E-02 2.005 1.00 1.00E+00 nonsynonymous SLITRK5

14 chr14_19598149 19598149 A/G 0.0122 0.0260 8.44E-03 0.46 0.94 1.00E+00 nonsynonymous OR4L1

14 rs3168891 35859480 T/G 0.0638 0.0370 1.27E-03 1.78 0.98 1.00E+00 nonsynonymous MBIP

14 rs45476195 72560612 T/C 0.0078 0.0202 4.15E-03 0.38 0.99 1.00E+00 nonsynonymous ZFYVE1

14 rs2286653 92743408 A/G 0.07643 0.1043 1.20E-02 0.7109 0.91 1.33E-01 nonsynonymous UBR7

15 chr15_19870496 19870496 A/G 0.1767 0.1409 9.38E-03 1.31 0.98 7.48E-05 nonsynonymous OR4M2

15 rs11549015 40022608 T/C 0.02241 0.01039 1.20E-02 2.184 1.00 1.00E+00 nonsynonymous EHD4

16 chr16_55974227 55974227 A/G 0.0048 0.0222 4.93E-05 0.21 0.97 1.00E+00 nonsynonymous CX3CL1

17 rs2289629 24984029 A/G 0.07734 0.05716 3.45E-02 1.383 0.96 7.15E-01 nonsynonymous SSH2

17 rs62079540 30703553 T/C 0.0421 0.0625 1.34E-02 0.6592 0.99 7.38E-01 nonsynonymous SLFN11

17 rs4624233 36209487 A/G 0.3123 0.3761 3.42E-04 0.75 0.98 2.02E-02 nonsynonymous KRT28

17 rs2305556 36925250 C/T 0.03696 0.06269 1.41E-03 0.5739 0.99 7.39E-01 nonsynonymous KRT15

17 rs13306087 58910142 A/G 0.01603 0.006657 1.89E-02 2.43 1.00 1.00E+00 nonsynonymous ACE


14

17 rs41295025 59342282 T/C 0.01876 0.009716 4.32E-02 1.948 0.99 1.00E+00 nonsynonymous CSHL1

17 rs11652075 75793488 T/C 0.4367 0.4967 2.32E-03 0.79 0.90 8.71E-01 nonsynonymous CARD14

18 rs2303507 32652881 A/G 0.1466 0.1104 3.98E-03 1.38 0.99 1.00E+00 nonsynonymous C18orf10

19 rs2287003 1992032 T/C 0.34 0.296 1.33E-02 1.225 0.95 9.26E-01 nonsynonymous DKFZp586A1021

19 rs11666450 8103865 T/C 0.0572 0.0362 8.82E-03 1.62 0.98 1.00E+00 nonsynonymous FBN3

19 rs3815746 9940093 T/C 0.2439 0.2941 2.99E-03 0.77 0.95 5.06E-01 nonsynonymous COL5A3

19 chr19_10993315 10993315 A/G 0.03075 0.01575 1.11E-02 1.983 0.90 1.00E+00 nonsynonymous SMARCA4

19 chr19_12915615 12915615 C/A 0.006435 0.01711 6.90E-03 0.372 0.99 1.00E+00 nonsynonymous CALR

19 rs2108622 15851431 T/C 0.2789 0.2252 9.88E-04 1.33 0.99 5.05E-01 nonsynonymous CYP4F2

19 chr19_41034408 41034408 A/G 0.01811 0.008197 2.13E-02 2.232 0.99 1.00E+00 nonsynonymous NPHS1

19 chr19_45770034 45770034 A/G 0.02211 0.01049 1.55E-02 2.131 0.99 1.00E+00 nonsynonymous SPTBN3

19 rs2288892 56220702 T/C 0.03096 0.04947 1.22E-02 0.6138 0.96 6.68E-01 nonsynonymous KLK11

20 rs2227275 43359987 T/C 0.0872 0.1228 1.84E-03 0.68 0.99 4.72E-01 nonsynonymous MATN4

20 rs707555 55571301 G/C 0.1904 0.2251 2.27E-02 0.8096 0.98 2.65E-01 nonsynonymous PCK1

21 chr21_36506176 36506176 A/C 0.04322 0.02795 2.97E-02 1.571 0.97 4.04E-01 nonsynonymous DOPEY2

22 rs5763269 28215473 T/C 0.1060 0.0770 7.42E-03 1.42 0.99 1.01E-01 nonsynonymous NEFH

Allele, minor allele/major allele F_A, minor allele frequency in cases F_U, minor allele frequency in controls


15

Supplementary Table 7. 742 genes by gene-based analysis from exome sequencing and targeted sequencing data Supplementary Table 8. Targeted sequencing of 565 immune related genes (not included psoriasis GWAS loci) and results of gene-based test Supplementary Table 9. Targeted sequencing of 57 genes in psoriasis GWAS loci and results of gene-based test


16

Supplementary Table 10. Genotype concordance between targeted sequencing and genotyping by Sequenom Concordance rate Individuals Proportion (%) <0.9 0 0 0.0-0.95 3 0.31 0.95-0.99 2 0.20 >=0.99 970 99.49

975 individuals and 27 SNVs


17

Supplementary Table 11. Common and low frequency nonsynonymous SNVs with P < 0.01 in targeted sequencing

Chr SNP BP(hg18) Allele Targeted sequencing

Exome sequencing Gene Function

F_A F_U P OR HWE F_A F_U P OR HWE

1 rs512208 150818909 A/C 0.323 0.276 1.75E-23 1.25 2.57E-02

0.328 0.304 1.77E-01 1.12 0.71 LCE3D c.G128T/p.G43V

4 rs2395617 35393698 A/C 0.027 0.016 3.52E-16 1.79 3.01E-01

0.033 0.014 1.00E-03 2.38 1 DEF6 c.A95C/p.N32T

3 rs27044 96144608 C/G 0.477 0.517 3.31E-15 0.85 6.73E-02

0.472 0.476 8.17E-01 0.98 0.64 ERAP1 c.C1624G/p.Q542E

3 rs26653 96165006 G/C 0.420 0.456 1.32E-12 0.87 2.06E-01

0.409 0.416 6.92E-01 0.97 1 ERAP1 c.G380C/p.R127P

1 chr1:67421184 67421184 A/G 0.036 0.048 3.32E-09 0.74 3.46E-02

0.030 0.058 1.62E-04 0.50 0.71 IL23R c.G445A/p.G149R

12 rs72474224 19661612 T/C 0.057 0.044 3.72E-09 1.32 9.53E-03

0.079 0.052 3.08E-03 1.57 0.69 GJB2 c.G109A/p.V37I

17 rs12459008 58146601 T/A 0.331 0.357 2.26E-07 0.89 1.38E-03

0.282 0.361 4.39E-04 0.70 0.92 ZNF816A c.T239A/p.I80N

17 rs1047781 53898443 T/A 0.473 0.449 4.22E-06 1.10 1.19E-01

0.453 0.433 2.83E-01 1.08 0.09 FUT2 c.A418T/p.I140F

1 chr1:151000000 151000000 G/C 0.049 0.059 1.16E-05 0.82 6.49E-01

0.045 0.072 2.06E-03 0.61 1 KPRP c.C1312G/p.P438A

2 rs2240543 241715462 G/A 0.225 0.244 1.61E-05 0.90 7.74E-01

0.207 0.206 9.82E-01 1.00 0.47 PASK c.T170C/p.L57S

17 rs11652075 75793488 T/C 0.462 0.482 1.10E-04 0.92 5.81E-04

0.437 0.497 2.32E-03 0.79 0.87 CARD14 c.C2458T/p.R820W

15 chr17:58910161 58910161 G/A 0.032 0.026 1.95E-04 1.27 1.33E-01

0.026 0.025 8.48E-01 1.05 1 ACE c.A479G/p.N160S

5 rs12675375 22040890 T/C 0.399 0.381 2.31E-04 1.08 5.17E-02

0.419 0.379 3.41E-02 1.18 0.003 HR c.G1010A/p.G337D

1 rs41268492 151037145 A/G 0.339 0.321 2.32E-04 1.09 5.02E-01

0.379 0.332 4.00E-02 1.23 0.45 LCE1D c.G251A/p.R84H

1 rs866484 157253101 G/C 0.325 0.308 4.03E-04 1.08 5.23E-03

0.334 0.336 9.09E-01 0.99 0.34 IFI16 c.G536C/p.S179T

3 rs1042779 52796051 G/A 0.419 0.437 4.38E-04 0.93 2.21E-02

0.392 0.406 4.37E-01 0.94 0.74 ITIH1 c.A446G/p.Q149R

11 rs2066807 55026949 G/C 0.030 0.037 6.37E-04 0.82 6.67E-01

0.035 0.031 5.98E-01 1.12 0.48 STAT2 c.G408C/p.M136I

11 rs7295376 6433029 C/G 0.116 0.106 7.47E-04 1.12 7.88E-01

0.117 0.118 9.14E-01 0.99 0.26 TAPBPL c.G451C/p.G151R

2 rs2234671 218737353 G/C 0.089 0.099 1.39E-03 0.90 9.55E-01

0.079 0.085 5.41E-01 0.92 0.13 IL8RA c.G827C/p.S276T

2 rs2005771 241714829 T/C 0.202 0.214 1.73E-03 0.92 4.89E-01

0.204 0.202 8.79E-01 1.01 0.47 PASK c.G803A/p.G268D

1 rs1288401 53326342 C/T 0.279 0.294 2.20E-03 0.93 1.00E-03

0.245 0.269 1.43E-01 0.88 0.84 SLC1A7 c.A569G/p.Q190R

2 rs6780013 47427122 A/G 0.361 0.346 2.45E-03 1.07 2.05E-04

0.107 0.208 3.13E-01 0.46 0.40 PTPN23 c.G2830A/p.A944T


18

1 rs2230677 29347981 G/C 0.168 0.157 2.72E-03 1.09 3.22E-01

0.170 0.147 9.54E-02 1.19 0.43 SFRS4 c.G1013C/p.G338A

7 rs2270889 2801557 T/C 0.009 0.012 2.75E-03 0.74 4.08E-01

0.010 0.009 7.07E-01 1.16 1 KIAA0020 c.G1439A/p.R480Q

3 rs17059569 58606361 A/G 0.013 0.017 2.95E-03 0.78 5.30E-01

0.012 0.018 1.66E-01 0.65 1 FAM3D c.C178T/p.P60S

2 rs10206753 102334794 C/T 0.159 0.148 3.03E-03 1.09 5.12E-01

0.146 0.127 3.09E-01 1.17 0.81 IL1RL1 c.T1652C/p.L551S

2 rs5743509 36373728 T/C 0.048 0.042 3.38E-03 1.16 2.15E-02

0.046 0.049 6.95E-01 0.93 0.39 BPI c.C587T/p.A196V

2 chr3:189379961 189379961 A/C 0.013 0.017 3.55E-03 0.78 5.27E-01

0.012 0.020 1.10E-01 0.61 0.22 UNQ1948 c.C296A/p.A99D

19 rs12977062 59447734 T/C 0.016 0.020 3.98E-03 0.80 1.00E+00

0.017 0.022 3.48E-01 0.77 1 LILRB5 c.G1324A/p.A442T

1 chr1:152017935 152017935 G/C 0.017 0.013 4.15E-03 1.27 1.00E+00

0.018 0.007 1.69E-02 2.49 1 SLC27A3 c.C1737G/p.C579W

19 chr19:9946062 9946062 T/C 0.106 0.114 5.01E-03 0.91 1.09E-01

0.108 0.115 6.00E-01 0.93 0.83 COL5A3 c.G3365A/p.R1122H

16 rs2066964 75786539 C/G 0.479 0.493 5.21E-03 0.94 3.29E-01

0.467 0.486 3.09E-01 0.93 1 CARD14 c.G930C/p.R310S

20 rs678 52796021 T/A 0.383 0.397 5.36E-03 0.94 7.44E-04

0.370 0.379 6.17E-01 0.96 0.74 ITIH1 c.A416T/p.E139V

1 chr1:52596134 52596134 G/C 0.036 0.041 5.42E-03 0.86 6.98E-02

0.025 0.039 4.59E-02 0.65 0.61 CC2D1B c.G124C/p.V42L

6 rs1801968 131620722 G/C 0.101 0.093 5.71E-03 1.10 6.74E-01

0.074 0.106 2.89E-03 0.68 0.067 TOR1A c.G646C/p.D216H

1 rs10999147 71550864 G/A 0.147 0.158 6.55E-03 0.92 6.62E-01

0.153 0.124 2.74E-02 1.27 0.10 AIFM2 c.T404C/p.M135T

19 rs4988956 102334439 A/G 0.150 0.140 7.30E-03 1.08 3.14E-01

0.146 0.137 4.87E-01 1.08 0.14 IL1RL1 c.G1297A/p.A433T

12 rs1867380 56263573 A/G 0.145 0.154 7.37E-03 0.93 2.16E-02

0.158 0.151 5.84E-01 1.06 1 AQP9 c.A835G/p.T279A

5 chr7:150566057 150566057 A/C 0.010 0.013 7.88E-03 0.78 2.38E-01

0.005 0.014 2.90E-02 0.39 1 CSGLCA-T c.C1676A/p.T559K

8 chr9:302104 302104 A/G 0.024 0.029 8.07E-03 0.85 3.61E-01

0.020 0.031 6.70E-02 0.65 0.02 DOCK8 c.G475A/p.E159K

19 rs10192157 102334788 T/C 0.151 0.141 8.22E-03 1.08 8.02E-01

0.147 0.130 3.51E-01 1.15 0.27 IL1RL1 c.C1646T/p.T549I

13 rs745400 2213549 G/A 0.298 0.285 8.37E-03 1.06 9.14E-04

0.272 0.269 8.50E-01 1.02 0.45 SGSM2 c.G713A/p.R238K

19 rs10192036 102334643 A/C 0.147 0.138 9.25E-03 1.08 2.35E-04

0.143 0.133 4.48E-01 1.09 0.50 IL1RL1 c.C1501A/p.Q501K

17 rs57088011 58146199 C/G 0.085 0.092 9.56E-03 0.91 5.41E-01

0.066 0.088 5.98E-02 0.74 1 ZNF816A c.C641G/p.S214C

10 chr11:71406470 71406470 C/G 0.032 0.028 9.62E-03 1.17 9.24E-02

0.030 0.035 4.80E-01 0.86 0.19 NUMA1 c.C1030G/p.L344V

3 rs13787 106536878 C/G 0.329 0.317 9.77E-03 1.06 4.70E-01

0.351 0.347 8.35E-01 1.02 0.72 PPA2 c.G348C/p.K116N

1 rs2508490 119604889 A/G 0.150 0.140 9.82E-03 1.08 4.96E-02

0.128 0.090 4.43E-03 1.47 1 OAF c.G650A/p.R217H


19



20

Supplementary Table 12. Association results of 2 rare variants by condition on the common variant in FUT2

CHR SNV (hg18) Allele Combined Conditional analysis

Gene F_A F_U P OR Condition on P OR

19 chr19_53898296 T/C 0.001919 0.0005324 5.51E-05 3.61(1.85-7.04) rs1047781 8.45E-05 4.036 FUT2 19 chr19_53898541 G/C 0.0006572 9.50E-05 2.92E-03 6.92(1.57-30.45) rs1047781 0.01153 6.755 FUT2



21

Supplementary Table 13. (a) Replication results of known nonsynonymous SNVs in this study

Chr Genes SNVs Allele Exome sequencing

Targeted sequencing

Combined

F_A F_U P OR

F_A F_U P OR

F_A F_U P OR

1 IL23R rs11209026 N/A

1 IL23R rs7530511 T/C 0.0173 0.0213 4.41E-01 0.81

0.0186 0.0177 5.45E-01 1.05

0.0185 0.0180 7.00E-01 1.02

5 ERAP1 rs30187 C/T 0.4477 0.4448 8.75E-01 1.01

0.4365 0.4450 3.53E-01 0.98

0.4393 0.4450 5.17E-01 0.99

5 IL13 rs20541 T/C 0.2926 0.3049 4.70E-01 0.94 0.2609 0.2724 1.17E-02 0.94 0.2633 0.2746 1.05E-02 0.94

6 TRAF3IP2 rs33980500 T/C 0.0034 0.0008 2.22E-01 4.53

0.0036 0.0022 1.17E-02 1.62

0.0036 0.0021 5.32E-03 1.69

17 CARD14 rs11652075 T/C 0.4367 0.4967 2.32E-03 0.79

0.4621 0.4819 1.10E-04 0.92

0.4605 0.4828 6.40E-06 0.91

19 TYK2 rs34536443 N/A Allele, minor allele/major allele

F_A, minor allele frequency in cases F_U, minor allele frequency in controls N/A, monomorphic in the individuals of this study (b) Further validation of rs11652075 within CARD14 by genotyping in additional 4,480 cases and 6,521 controls SNV Allele

Genotyping Combined F_A F_U P OR P OR

rs11652075 T/C 0.4716 0.4964 1.47E-04 0.91 3.46E-09 0.91 Allele, minor allele/major allele F_A, minor allele frequency in cases F_U, minor allele frequency in controls


22

Supplementary Table 14. Haplotype analysis between GWAS SNPs and missense SNVs Note: yellow cells are minor allele, red characters are risk allele. (a) LCE3D (3,980 cases and 3,152 controls) GWAS missense

Freq. Cases Controls P value OR (95%CI) rs4085613 rs512208 A C 0.391 4,573(36.6%) 4,728(41.8%) 3.41E-16 0.78(0.75-0.83) C A 0.305 4,099(32.8%) 3,161(27.9%) 3.35E-16 1.26(1.19-1.33) C C 0.302 3,785(30.3%) 3,406.8(30.1%) 0.7376 1.01(0.96-1.07) A A 0.002 29(0.2%) 16(0.1%) 0.1103 1.64(0.89-3.03)

(b) ERAP1 (5,693 cases and 5,630 controls) missense missense GWAS

Freq. Cases Controls P value OR (95%CI) rs27044 rs26653 rs151823 G C A 0.498 6,234(51%) 5,960(48.7%) 4.00E-04 1.09(1.04-1.15) C G C 0.414 4,929(40.3%) 5,213(42.6%) 2.00E-04 0.91(0.86-0.96) C C C 0.055 683(5.6%) 667(5.5%) 0.653 1.03(0.92-1.15) G C C 0.017 196(1.6%) 212(1.7%) 0.4225 0.92(0.76-1.12) C G A 0.008 100(0.8%) 92(0.8%) 0.5669 1.09(0.82-1.45) C C A 0.004 43(0.3%) 54(0.4%) 0.2495 0.80(0.53-1.19) G G C 0.004 50(0.4%) 40(0.3%) 0.3112 1.25(0.83-1.90)


23

(c) ZNF816A (5,601 cases and 5,620 controls) GWAS missense

Freq. Cases Controls P value OR (95%CI) rs9304742 rs12459008 T A 0.656 8,195(67.0%) 7,862(64.2%) 4.50E-06 1.13(1.07-1.19) C T 0.336 3,945(32.3%) 4,271(34.9%) 1.30E-05 0.89(0.84-0.94) C A 0.004 47(0.4%) 54(0.4%) 0.5001 0.87(0.59-1.29) T T 0.004 41(0.3%) 53(0.4%) 0.2188 0.77(0.51-1.16)


24

Supplementary Table 15. Further haplotype analysis in GJB2 gwas missense

Case Control P OR' Heterogeneity test

rs3751385 rs72474224 P OR C C 4541(48.4%) 3406(52.2%) Reference

T C 4257(45.4%) 2790(42.8%) 5.00E-05 1.14(1.07-1.22) 0.022 1.18

T T 578(6.2%) 320(4.9%) 3.20E-05 1.36(1.17-1.56) C T 10(0.1%) 7(0.1%) 0.89 1.07(0.41-2.82)

OR’ refer to Chi Square test for different haplotype compared with wild-genotype haplotype (reference)


25

Supplementary Table 16. Replication of 133 nonsynonymous SNVs by targeted sequencing

CHR SNP BP (hg18) Allele F_A F_U P OR

Sample

covered HWE function gene

1 chr1_1445449 1445449 T/C 0.01286 0.01156 2.76E-01 1.114 0.85 6.31E-01 nonsynonymous ATAD3A


1 rs10909820 3797310 A/C 0.1561 0.1531 4.10E-01 1.023 0.98 7.09E-22 nonsynonymous C1orf174

1 rs5746026 12175649 A/G 0.03797 0.03861 7.42E-01 0.9827 0.97 5.22E-02 nonsynonymous TNFRSF1B

1 chr1_22182802 22182802 T/C 0.03081 0.03244 3.60E-01 0.9484 0.98 8.71E-01 nonsynonymous ELA3B

1 rs3795424 32933231 G/T 0.2399 0.2367 5.95E-01 1.018 0.51 2.33E-30 nonsynonymous SYNC

1 chr1_36527627 36527627 G/C 0.03195 0.03122 6.80E-01 1.024 0.98 3.13E-01 nonsynonymous THRAP3

1 chr1_52596134 52596134 G/C 0.03559 0.04098 5.42E-03 0.8637 0.99 6.98E-02 nonsynonymous CC2D1B

1 rs2495477 55291055 G/A 0.2813 0.2872 2.03E-01 0.9715 0.96 2.85E-03 nonsynonymous PCSK9

1 rs17117720 58777205 A/G 0.122 0.1234 6.64E-01 0.9867 0.94 1.05E-27 nonsynonymous OMA1

1 chr1_67421184 67421184 A/G 0.0362 0.04834 3.32E-09 0.7393 0.97 3.46E-02 nonsynonymous IL23R

1 chr1_91515129 91515129 T/C 0.01267 0.01498 4.95E-02 0.8434 0.96 1.00E+00 nonsynonymous HFM1

1 rs45455292 111759093 C/G 0.06288 0.06277 9.67E-01 1.002 0.92 3.97E-02 nonsynonymous OVGP1

1 rs2798901 143590621 G/A 0.07106 0.1084 4.59E-05 0.629 0.14 2.40E-07 nonsynonymous PDE4DIP

1 rs2275249 145225944 G/C 0.1975 0.192 1.72E-01 1.035 0.99 2.69E-01 nonsynonymous CHD1L

1 chr1_151000000 151000000 G/C 0.04872 0.05867 1.16E-05 0.8217 0.99 6.49E-01 nonsynonymous KPRP

1 rs753856 159762758 G/C 0.177 0.1868 1.42E-02 0.9364 0.94 1.89E-02 nonsynonymous HSPA6

1 rs2272792 165096146 T/C 0.1325 0.132 8.92E-01 1.004 0.94 9.19E-34 nonsynonymous TADA1L

1 rs6692219 178256207 C/G 0.04133 0.04007 5.34E-01 1.033 0.97 3.50E-01 nonsynonymous CEP350

1 rs2295950 183442460 C/A 0.2277 0.2184 1.67E-01 1.055 0.29 1.03E-37 nonsynonymous C1orf26

1 rs12139527 199275805 G/A 0.1957 0.2007 3.55E-01 0.9695 0.58 1.63E-17 nonsynonymous CACNA1S


26

1 rs2275866 199618044 A/T 0.1578 0.1516 2.62E-01 1.049 0.45 3.11E-39 nonsynonymous LAD1

1 chr1_239824570 239824570 T/C 0.0101 0.01101 3.84E-01 0.9171 0.97 6.33E-01 nonsynonymous OPN3

2 rs1879761 26604273 A/G 0.2208 0.2229 6.40E-01 0.9884 0.94 4.38E-25 nonsynonymous OTOF

2 rs1881421 29269870 G/C 0.2642 0.2639 9.42E-01 1.002 0.99 2.03E-01 nonsynonymous ALK

2 rs1881420 29269985 T/C 0.2396 0.2398 9.66E-01 0.999 0.95 2.02E-47 nonsynonymous ALK

2 chr2_152027704 152027704 A/G 0.0176 0.01884 3.58E-01 0.9329 0.99 1.63E-01 nonsynonymous RIF1

2 rs2123465 152028364 G/A 0.2106 0.2161 1.81E-01 0.9674 0.98 6.74E-01 nonsynonymous RIF1

2 rs3762568 207339706 A/G 0.02465 0.02456 9.56E-01 1.004 0.96 1.32E-01 nonsynonymous FASTKD2

2 rs17235409 218967976 A/G 0.1335 0.1315 5.71E-01 1.017 0.97 1.23E-08 nonsynonymous SLC11A1

2 rs1035834 230569763 T/G 0.1126 0.1148 4.84E-01 0.9779 0.98 1.53E-26 nonsynonymous FBXO36

2 chr2_239726340 239726340 T/C 0.0449 0.04227 2.02E-01 1.065 0.99 4.54E-01 nonsynonymous HDAC4

2 chr2_240714874 240714874 T/C 0.08684 0.08721 8.98E-01 0.9954 0.99 1.02E-18 nonsynonymous MYEOV2

2 rs757978 242019774 T/C 0.01851 0.01828 8.66E-01 1.013 0.97 2.50E-01 nonsynonymous FARP2

3 rs455863 9931279 A/G 0.06879 0.06923 8.65E-01 0.9932 0.96 5.44E-09 nonsynonymous IL17RE

3 rs708567 9935070 T/C 0.07046 0.07043 9.90E-01 1.001 0.97 1.71E-03 nonsynonymous IL17RC

3 rs34833812 30688623 T/C 0.01965 0.02315 1.70E-02 0.8459 0.98 4.96E-01 nonsynonymous TGFBR2

3 rs35217513 40532447 A/C 0.1215 0.1196 5.66E-01 1.018 0.97 2.43E-31 nonsynonymous ZNF620

3 chr3_65413949 65413949 T/C 0.01017 0.01088 4.91E-01 0.9341 0.91 6.31E-01 nonsynonymous MAGI1

3 rs41272317 133820167 A/C 0.07226 0.07345 6.49E-01 0.9825 0.99 1.14E-02 nonsynonymous ACAD11

4 rs34860182 6976138 G/C 0.03001 0.02866 4.33E-01 1.048 0.98 5.85E-01 nonsynonymous TBC1D14

4 rs10007352 10056777 T/C 0.1162 0.1165 9.23E-01 0.9969 0.96 9.92E-34 nonsynonymous ZNF518B

4 rs17013285 88986032 A/G 0.2473 0.2392 6.20E-02 1.045 0.98 2.16E-05 nonsynonymous MEPE

4 chr4_187390284 187390284 T/C 0.02094 0.01921 2.23E-01 1.092 0.98 2.72E-01 nonsynonymous KLKB1

5 rs10941112 34040464 T/C 0.2958 0.2955 9.61E-01 1.001 0.93 3.87E-79 nonsynonymous AMACR


27


5 chr5_55515162 55515162 G/C 0.01081 0.01014 5.15E-01 1.067 0.97 6.28E-01 nonsynonymous ANKRD55

5 rs2240696 140148254 A/G 0.4241 0.425 8.60E-01 0.9964 0.98 4.30E-01 nonsynonymous PCDHA1

5 rs2240695 140148335 G/T 0.4386 0.4402 7.47E-01 0.9934 0.96 1.06E-03 nonsynonymous PCDHA1

5 rs11167600 140155049 G/C 0.4282 0.4292 8.45E-01 0.996 0.98 8.98E-02 nonsynonymous PCDHA2

5 rs4141841 140183616 C/T 0.433 0.4344 7.72E-01 0.9941 0.97 4.55E-01 nonsynonymous PCDHA5

5 rs17844301 140189068 C/A 0.06339 0.06345 9.86E-01 0.9989 0.44 6.34E-03 nonsynonymous PCDHA6

5 rs17844323 140208597 A/C 0.1297 0.1267 3.68E-01 1.028 0.97 1.87E-02 nonsynonymous PCDHA9

5 rs11435 145422326 A/G 0.2514 0.2536 6.33E-01 0.9884 0.90 7.42E-104 nonsynonymous SH3RF2

5 rs4958531 151752031 C/T 0.1697 0.1541 2.49E-02 1.122 0.24 2.06E-11 nonsynonymous NMUR2

5 rs4958532 151752045 A/G 0.04829 0.04405 4.77E-02 1.101 0.71 5.05E-05 nonsynonymous NMUR2

5 rs1895245 151752248 T/G 0.05172 0.04681 2.74E-02 1.11 0.95 1.71E-04 nonsynonymous NMUR2

5 rs4958535 151755257 G/C 0.04929 0.04526 6.13E-02 1.094 0.98 7.25E-01 nonsynonymous NMUR2

6 rs2395617 35393698 A/C 0.02749 0.01554 3.52E-16 1.791 0.99 3.01E-01 nonsynonymous DEF6

6 chr6_47085808 47085808 T/A 0.04038 0.03946 7.87E-01 1.024 0.35 9.27E-03 nonsynonymous GPR110

6 rs1932618 69723405 A/G 0.1067 0.1052 6.17E-01 1.017 0.97 7.83E-12 nonsynonymous BAI3

6 rs3747787 107074471 C/T 0.2279 0.2265 8.25E-01 1.008 0.47 1.61E-20 nonsynonymous AIM1


6 chr6_138680135 138680135 G/A 0.07803 0.07221 1.99E-01 1.087 0.35 4.28E-04 nonsynonymous KIAA1244

6 rs73606794 150039036 A/C 0.02375 0.02319 7.18E-01 1.025 0.90 9.44E-02 stoploss LATS1

6 rs56149740 150047208 T/G 0.02457 0.02449 9.59E-01 1.003 0.95 1.32E-01 nonsynonymous LATS1

6 rs2027063 169886153 A/C 0.03407 0.03479 6.94E-01 0.9785 0.99 1.74E-01 nonsynonymous TCTE3

7 chr7_2549433 2549433 T/C 0.2597 0.2575 6.32E-01 1.011 0.95 1.61E-35 nonsynonymous C7orf27



28

7 chr7_34052446 34052446 A/G 0.08939 0.09097 5.88E-01 0.981 0.98 2.30E-12 nonsynonymous BMPER

7 chr7_133582908 133582908 T/C 0.0148 0.0139 4.50E-01 1.066 0.99 7.13E-01 nonsynonymous LRGUK

7 rs2290971 148343025 A/G 0.07484 0.07386 7.15E-01 1.014 0.97 2.13E-06 nonsynonymous PDIA4

7 rs1130496 157652656 T/C 0.3401 0.3395 9.14E-01 1.002 0.91 1.65E-75 nonsynonymous PTPRN2

8 chr8_11740062 11740062 G/T 0.1009 0.09703 3.89E-01 1.045 0.46 1.29E-06 nonsynonymous CTSB

8 rs1801280 18302134 C/T 0.12 0.1179 7.25E-01 1.02 0.31 2.94E-11 nonsynonymous NAT2

8 chr8_22035968 22035968 A/C 0.01697 0.01718 8.71E-01 0.9874 0.98 5.37E-01 nonsynonymous HR

8 chr8_69162517 69162517 T/G 0.09458 0.09604 6.27E-01 0.9833 0.56 5.39E-23 nonsynonymous PREX2

8 rs920829 73140257 T/C 0.2833 0.2823 8.20E-01 1.005 0.96 3.01E-24 nonsynonymous TRPA1

9 rs3814541 108729573 T/C 0.09014 0.08968 8.74E-01 1.006 0.97 8.26E-10 nonsynonymous ZNF462

9 rs1801968 131620722 G/C 0.1011 0.09278 5.71E-03 1.099 0.92 7.18E-01 nonsynonymous TOR1A

10 chr10_13257566 13257566 G/C 0.01144 0.01139 9.59E-01 1.005 0.97 1.00E+00 nonsynonymous MCM10

10 rs3750575 74808697 T/C 0.04734 0.04775 8.49E-01 0.991 0.99 1.00E-02 nonsynonymous ANXA7

10 rs11556392 99429546 C/A 0.05777 0.05872 7.06E-01 0.9829 0.87 9.22E-01 nonsynonymous AVPI1

10 chr10_105787507 105787507 C/A 0.02501 0.02453 7.97E-01 1.02 0.70 4.43E-01 nonsynonymous COL17A1

10 chr10_108449102 108449102 T/C 0.009687 0.01066 3.42E-01 0.9082 0.98 6.30E-01 nonsynonymous SORCS1

10 chr10_115937861 115937861 A/G 0.02501 0.02573 6.55E-01 0.9714 0.97 5.36E-01 nonsynonymous TDRD1

11 rs2061586 548884 C/T 0.2018 0.2014 9.16E-01 1.003 0.80 2.05E-06 nonsynonymous C11orf35

11 rs10768450 4977408 T/C 0.0771 0.07267 9.76E-02 1.066 0.78 1.15E-16 nonsynonymous OR51L1

11 rs1965207 6869819 C/T 0.08233 0.08374 7.18E-01 0.9816 0.51 7.32E-04 nonsynonymous OR2D2

11 rs1453547 58946488 A/G 0.1339 0.1291 1.64E-01 1.043 0.96 1.06E-36 nonsynonymous OR5A2

11 chr11_64577311 64577311 T/C 0.01991 0.0208 5.36E-01 0.9565 0.98 1.00E+00 nonsynonymous NAALADL1


11 rs17099008 101987714 G/T 0.2114 0.2185 2.19E-01 0.9587 0.52 1.88E-24 nonsynonymous MMP20


29

11 rs2305830 116771522 G/C 0.2574 0.2589 7.44E-01 0.9925 0.99 7.88E-03 nonsynonymous CEP164

11 chr11_123391517 123391517 T/C 0.1696 0.1709 7.17E-01 0.9902 0.97 4.21E-39 nonsynonymous OR10G4

12 rs1045546 6438168 T/C 0.01531 0.01454 5.34E-01 1.054 0.97 1.00E+00 nonsynonymous TAPBPL

12 rs10849482 6505535 A/G 0.01533 0.01439 4.42E-01 1.067 0.98 2.72E-01 nonsynonymous NCAPD2

12 chr12_45757822 45757822 G/C 0.03583 0.03427 4.02E-01 1.047 0.90 3.58E-01 nonsynonymous AMIGO2

12 rs2232405 51108409 G/A 0.09289 0.0908 4.82E-01 1.025 0.95 1.31E-01 nonsynonymous KRT75

12 rs2232387 51113875 T/C 0.09024 0.08724 2.95E-01 1.038 0.99 8.70E-02 nonsynonymous KRT75

12 rs925368 108875362 C/T 0.2005 0.2093 1.90E-01 0.9479 0.38 2.10E-32 nonsynonymous GIT2

12 rs3741466 115949647 T/C 0.1029 0.1018 7.18E-01 1.012 0.98 1.54E-06 nonsynonymous FBXW8

13 rs72474224 19661612 T/C 0.05661 0.04352 3.72E-09 1.319 0.97 9.53E-03 nonsynonymous GJB2

13 rs61729904 51263355 T/G 0.07382 0.081 3.93E-02 0.9043 0.64 2.53E-13 nonsynonymous DHRS12

13 chr13_87127473 87127473 A/T 0.02796 0.02615 3.95E-01 1.071 0.60 4.41E-01 nonsynonymous SLITRK5

14 chr14_19598149 19598149 A/G 0.01708 0.01825 3.90E-01 0.9351 0.95 7.88E-02 nonsynonymous OR4L1

14 rs3168891 35859480 T/G 0.05852 0.05467 1.12E-01 1.075 0.92 3.56E-06 nonsynonymous MBIP

14 rs45476195 72560612 T/C 0.0129 0.01209 4.75E-01 1.068 0.97 1.00E+00 nonsynonymous ZFYVE1

14 rs2286653 92743408 A/G 0.1003 0.09715 2.97E-01 1.036 0.97 4.24E-03 nonsynonymous UBR7

15 chr15_19870496 19870496 A/G 0.1624 0.1669 2.42E-01 0.9678 0.94 3.80E-72 nonsynonymous OR4M2

15 rs11549015 40022608 T/C 0.01662 0.01672 9.42E-01 0.9943 0.98 1.17E-01 nonsynonymous EHD4

16 chr16_55974227 55974227 A/G 0.0137 0.01476 3.77E-01 0.9267 0.97 7.26E-01 nonsynonymous CX3CL1

17 rs2289629 24984029 A/G 0.07086 0.06832 3.29E-01 1.04 0.97 2.45E-05 nonsynonymous SSH2

17 rs62079540 30703553 T/C 0.04942 0.05232 1.94E-01 0.9418 0.98 6.56E-04 nonsynonymous SLFN11

17 rs4624233 36209487 A/G 0.3193 0.3207 7.79E-01 0.9938 0.95 1.82E-22 nonsynonymous KRT28

17 rs2305556 36925250 C/T 0.1049 0.1025 5.70E-01 1.026 0.53 1.34E-06 nonsynonymous KRT15

17 rs13306087 58910142 A/G 0.009724 0.01114 1.74E-01 0.8718 0.96 6.33E-01 nonsynonymous ACE


30

17 rs41295025 59342282 T/C 0.01305 0.01471 1.65E-01 0.8856 0.90 2.75E-01 nonsynonymous CSHL1

17 rs11652075 75793488 T/C 0.4621 0.4819 1.10E-04 0.9237 0.96 5.81E-06 nonsynonymous CARD14


19 rs2287003 1992032 T/C 0.3308 0.3332 6.18E-01 0.9891 0.93 3.32E-01 nonsynonymous DKFZp586A1021

19 rs11666450 8103865 T/C 0.05325 0.05351 9.12E-01 0.9949 0.95 2.63E-01 nonsynonymous FBN3

19 rs3815746 9940093 T/C 0.2628 0.2561 1.30E-01 1.036 0.98 1.05E-01 nonsynonymous COL5A3

19 chr19_10993315 10993315 A/G 0.02886 0.02797 5.97E-01 1.033 0.98 1.28E-01 nonsynonymous SMARCA4

19 chr19_12915615 12915615 C/A 0.04059 0.04254 5.77E-01 0.9522 0.36 2.82E-01 nonsynonymous CALR

19 rs2108622 15851431 T/C 0.2302 0.2269 4.45E-01 1.019 0.94 3.36E-92 nonsynonymous CYP4F2

19 chr19_41034408 41034408 A/G 0.01035 0.009295 2.96E-01 1.115 0.96 1.00E+00 nonsynonymous NPHS1

19 chr19_45770034 45770034 A/G 0.01487 0.01577 4.69E-01 0.9417 0.97 1.00E+00 nonsynonymous SPTBN3

19 rs2288892 56220702 T/C 0.04051 0.03957 6.40E-01 1.025 0.96 2.75E-01 nonsynonymous KLK11

20 rs2227275 43359987 T/C 0.1113 0.1163 1.25E-01 0.9518 0.96 6.95E-21 nonsynonymous MATN4

20 rs707555 55571301 G/C 0.2192 0.2114 6.19E-02 1.047 0.97 2.88E-03 nonsynonymous PCK1

21 chr21_36506176 36506176 A/C 0.03717 0.03751 8.59E-01 0.9904 0.96 5.64E-03 nonsynonymous DOPEY2

22 rs5763269 28215473 T/C 0.09475 0.09159 2.87E-01 1.038 0.97 5.85E-12 nonsynonymous NEFH



31

Supplementary Table 17. Gene-based analysis for IL23R and GJB2

Type Gene MIN_P_value MAF 5%, not weighted by function prediction

SKAT-O UNIQ SUMSTAT CALPHA VT FRQWGT BURDEN

All functional SNV IL23R 1.53E-06 1.53E-06 9.69E-01 3.13E-01 7.19E-01 6.56E-01 8.75E-01 3.75E-01 removed chr1_67421184 IL23R 3.03E-01 5.21E-01 9.39E-01 3.03E-01 5.76E-01 6.97E-01 7.58E-01 3.03E-01

All functional SNV GJB2 1.24E-05 1.24E-05 7.22E-01 7.22E-01 4.44E-01 4.44E-01 5.00E-01 7.22E-01 removed chr13_19661612 GJB2 5.19E-01 5.19E-01 9.33E-01 6.67E-01 5.33E-01 6.67E-01 6.67E-01 8.00E-01

Type Gene MIN_P_value MAF 5%, weighted by function prediction

SKAT-O UNIQ SUMSTAT CALPHA VT FRQWGT BURDEN aSum cmc wss collaps

All functional SNV IL23R 3.31E-08 3.31E-08 8.57E-01 1.14E-01 2.29E-01 8.67E-01 9.81E-01 9.52E-01 1.97E-05 1.76E-04 9.99E-04 3.86E-04

removed chr1_67421184 IL23R 9.09E-02 2.12E-01 8.53E-01 9.09E-02 1.75E-01 8.60E-01 9.72E-01 9.37E-01 3.50E-01 7.99E-01 5.56E-01 6.92E-01

All functional SNV GJB2 6.97E-07 6.97E-07 6.02E-01 5.57E-01 2.27E-01 4.43E-01 2.61E-01 1.36E-01 2.71E-06 3.53E-05 9.99E-04 1.41E-04

removed chr13_19661612 GJB2 8.47E-02 4.34E-01 5.57E-01 6.09E-01 2.70E-01 3.74E-01 2.43E-01 1.13E-01 5.00E-01 3.00E-01 5.96E-01 8.47E-02


32

Supplementary Table 18. Depth and coverage per gene Supplementary Table 19. Recovery rate of SNVs in 1000 Genomes Project Han Chinese population (1) exome sequencing

VAF # of 1000G SNV

in target # of SNV detected by targeted sequencing

Sensitivity

[0,0.02) 4159 3436 82.62% [0.02,0.05) 2962 2839 95.85% [0.05,0.1) 8257 7686 93.08% [0.1,0.2) 8601 7212 83.85% [0.2,0.3) 4951 4246 85.76% [0.3,0.4) 3969 3778 95.19% [0.4,0.5) 3138 3108 99.04% [0.5,0.6) 2644 2639 99.81% [0.6,0.7) 2274 2262 99.47% [0.7,0.8) 1898 1896 99.89% [0.8,0.9) 1774 1771 99.83% [0.9,1] 2445 2437 99.67%

(2) targeted sequencing

VAF # of 1000G

SNV in target # of SNV detected by targeted sequencing

Sensitivity

[0,0.02) 1,186 1,186 100.00% [0.02,0.05) 1,300 1,300 100.00% [0.05,0.1) 1,983 1,983 100.00% [0.1,0.2) 2,798 2,798 100.00% [0.2,0.3) 1,622 1,622 100.00% [0.3,0.4) 1,215 1,215 100.00% [0.4,0.5) 931 931 100.00% [0.5,0.6) 791 791 100.00% [0.6,0.7) 687 687 100.00% [0.7,0.8) 539 539 100.00% [0.8,0.9) 493 493 100.00% [0.9,1] 979 979 100.00%


33

Supplementary Figure 1. Description of the study design

First, we performed exome sequencing using 781 psoriasis cases and 676 controls. A total of 38,517 nonsynonymous SNVs with MAF > 0.1% was subjected to single variant association analysis and 133 nonsynonymous SNVs showed nominal association (P < 0.05). Multi-variant gene-based association analyses were also performed by using nonsynonymous SNVs with MAF < 5%, 742 genes were found to show P < 0.05. As validation, the 133 top nonsynonymous SNVs, 742 top genes as well as 622 immune disease genes (including 57 candidate genes within 44 psoriasis susceptibility loci reported by GWAS) were further analyzed in additional 9,946 cases and 9,906 controls through targeted sequencing analysis. A total of 3.2Mb coding sequences surrounding the targeted regions of 1,326 genes were captured and sequenced, 82,387 nonsynonymous SNVs were identified and enrolled in single variant and gene-based analyses.


34

Supplementary Figure 2. Depth distribution of sequencing

Figure on left is the distribution of per-base sequencing depth of all samples in target region. X-axis denotes sequencing depth, while Y-axis indicated the percentage of total target region under a given sequencing depth. Figure on right is cumulative depth distribution. X-axis denotes sequencing depth, and Y-axis indicated the fraction of bases that achieves at or above a given sequencing depth. (a) Depth of exome sequencing. (b) Depth of target sequencing.


35

Supplementary Figure 3. Manhattan plot of nonsynonymous SNVs in exome sequencing

Supplementary Figure 4. Manhattan plot of nonsynonymous SNVs in targeted sequencing


36

Supplementary Figure 5. Structure of the connexin 26 gap junction channel (GJB2) at 3.5 A resolution

Supplementary Figure 6. Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1)


37

Supplementary Figure 7. Power calculator in combined samples 10,727 cases and 10,582 controls


38

Supplementary Figure 8. PCA analysis in exome sequencing and targeted sequencing

(a) PCA analysis for ancestry with 1,457 exome sequencing samples; 1000 Genome Project data be used in order to quality control for sample.1st and 2nd principal component; X-axis is eigenvector 1st；Y-axis is eigenvector 2st, and all samples were in the CHB+JPT cluster.

(b) PCA analysis for ancestry with 19,852 target sequencing samples; 1000 Genome Project data be used in order to quality control for sample.1st and 2nd principal component; X-axis is eigenvector 1st；Y-axis is eigenvector 2st . Sample NH2034 was found float away from the cohort, and was discarded in the following analysis.


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