Supplementary Table 1. the Demographic of Participants and Clinical Phenotype in the Study

Supplementary information

Supplementary Tables

Supplementary Table 1. The demographic of participants and clinical phenotype in the study

Characteristic / GWAS cohort / GWAS Replication cohort / Imputation Replication cohort
patient / 242 / 178 / 162
age / 57.47±13.75 / 58.37±12.20 / 58.21±12.10
Control / 1,444 / 14,432 / 500
age / 50.62±16.96 / NA / NA

The number and average age of female subjects in GWAS and replication cohort are provided. NA: average age is not provided by Taiwan Biobank. The total collection of Taiwan BioBank currently includes64.89% female and 35.11% male, 19.64% of subjects are with age between 30-39; 22.2% with age between 40-49; 33.01% with age between 50-59; 25.15% with age above 60.

Supplementary Table 2.Quality control of participant data.

Number at start of QC / 628,132 SNPs
SNPs dropped during exclusion step :
only include SNPs with MAF ≥ 0.05 / 42,146 SNPs
includes SNPs with a 95% genotyping rate / 14,141 SNPs
SNPs to be excluded based on HWE test for CN (P≤0.0001) / 8,040 SNPs
APT calling QC / 14,980 SNPs
Number at end of QC / 548,825 SNPs

QC: Quality control; MAF: minor allele frequency; HWE: Hardy–Weinberg equilibrium; CN: Control; APT: Affymetrix Power Tools.

Supplementary Table 3: All SNPs (n=75) with P trend < 10−4 in the GWAS

Chr / SNP / Pisition / Gene / Allele / Risk Allele / RAF Patients / RAF Controls / Ptrend / Risk Allele OR (95% CI)
1 / rs7417430 / 62843575 / T/C / T / 0.5310 / 0.4332 / 6.53×10-5 / 1.481 (1.221-1.797)
1 / rs6671952 / 116220358 / VANGL1 / C/G / C / 0.1639 / 0.1039 / 9.28×10-5 / 1.691 (1.292-2.213)
1 / rs10494179 / 116239368 / CASQ2 / A/G / A / 0.3326 / 0.2490 / 9.76×10-5 / 1.504 (1.222-1.85)
1 / rs347295 / 162296956 / NOS1AP / G/A / G / 0.5269 / 0.4313 / 8.63×10-5 / 1.469 (1.211-1.781)
1 / rs347298 / 162297946 / NOS1AP / A/C / C / 0.5954 / 0.4948 / 3.85×10-5 / 1.503 (1.235-1.828)
1 / rs1056607 / 225611661 / LBR / C/T / C / 0.3071 / 0.2196 / 3.04×10-5 / 1.574 (1.273-1.947)
1 / rs16845946 / 226623766 / C/T / C / 0.1083 / 0.0580 / 3.25×10-5 / 1.973 (1.422-2.738)
2 / rs72777025 / 9699010 / T/C / T / 0.2261 / 0.1433 / 4.47×10-6 / 1.747 (1.378-2.215)
2 / rs10929589 / 9703439 / C/T / C / 0.2045 / 0.1328 / 3.85×10-5 / 1.679 (1.313-2.147)
2 / rs13390707 / 56877853 / T/C / C / 0.7116 / 0.6122 / 1.86×10-5 / 1.563 (1.266-1.93)
2 / rs6757997 / 56896324 / C/T / T / 0.7075 / 0.6098 / 2.75×10-5 / 1.548 (1.255-1.909)
3 / rs17008507 / 2198900 / CNTN4 / T/A / T / 0.3595 / 0.2720 / 9.41×10-5 / 1.502 (1.226-1.84)
3 / rs117802738 / 5060160 / A/G / A / 0.1136 / 0.0596 / 1.26×10-5 / 2.024 (1.47-2.789)
3 / rs9830571 / 23705238 / G/A / A / 0.9236 / 0.8564 / 4.83×10-5 / 2.025 (1.425-2.877)
3 / rs13079920 / 29445931 / RBMS3 / A/G / A / 0.3864 / 0.2953 / 3.96×10-5 / 1.502 (1.23-1.834)
3 / rs12486329 / 70445072 / G/A / G / 0.3021 / 0.2205 / 8.29×10-5 / 1.53 (1.235-1.895)
3 / rs3849491 / 76484183 / ROBO2 / C/T / C / 0.5664 / 0.4660 / 2.98×10-5 / 1.497 (1.232-1.818)
3 / rs7612860 / 76489848 / ROBO2 / C/T / C / 0.5000 / 0.4051 / 9.64×10-5 / 1.469 (1.21-1.783)
3 / rs769553 / 109205434 / FLJ25363 / G/A / G / 0.5248 / 0.4304 / 9.27×10-5 / 1.461 (1.205-1.773)
3 / rs77784139 / 148662742 / A/G / A / 0.1095 / 0.0531 / 1.06×10-6 / 2.195 (1.58-3.049)
3 / rs7648956 / 149447923 / C/T / T / 0.6033 / 0.5028 / 5.96×10-5 / 1.504 (1.236-1.83)
3 / rs951300 / 149455651 / G/A / A / 0.6639 / 0.5646 / 8.03×10-5 / 1.523 (1.242-1.868)
4 / rs117622645 / 52865442 / LRRC66 / T/C / C / 0.9461 / 0.8878 / 9.82×10-5 / 2.216 (1.468-3.345)
4 / rs10023906 / 75197803 / T/C / T / 0.1846 / 0.1162 / 3.54×10-5 / 1.723 (1.333-2.228)
4 / rs4320128 / 84287807 / A/G / A / 0.2490 / 0.1708 / 3.62×10-5 / 1.609 (1.281-2.021)
4 / rs10001661 / 89249372 / LOC101929118 / G/A / A / 0.6653 / 0.5305 / 3.28×10-8 / 1.759 (1.437-2.154)
4 / rs79218515 / 126920257 / T/C / T / 0.1281 / 0.0738 / 6.49×10-5 / 1.844 (1.365-2.491)
4 / rs36094697 / 126934079 / G/A / G / 0.1266 / 0.0721 / 5.17×10-5 / 1.865 (1.377-2.527)
4 / rs550111 / 127080561 / A/G / A / 0.1639 / 0.0902 / 5.98×10-7 / 1.977 (1.505-2.597)
5 / rs163818 / 14072057 / C/T / C / 0.1281 / 0.0651 / 1.09×10-6 / 2.108 (1.554-2.86)
6 / rs7763262 / 32424882 / T/C / T / 0.3554 / 0.2568 / 6.33×10-6 / 1.596 (1.301-1.957)
6 / rs9268877 / 32431147 / A/G / A / 0.5844 / 0.4734 / 9.08×10-6 / 1.564 (1.284-1.905)
6 / rs9269080 / 32440969 / G/A / G / 0.5768 / 0.4709 / 1.89×10-5 / 1.531 (1.26-1.861)
6 / rs9271090 / 32576247 / T/C / T / 0.2149 / 0.1411 / 2.42×10-5 / 1.666 (1.309-2.119)
6 / rs9271117 / 32576795 / C/T / C / 0.2137 / 0.1408 / 3.05×10-5 / 1.659 (1.303-2.112)
6 / rs9271160 / 32577646 / A/G / A / 0.2137 / 0.1371 / 9.62×10-6 / 1.711 (1.343-2.18)
6 / rs3129761 / 32585504 / G/C / G / 0.4519 / 0.3511 / 3.35×10-5 / 1.524 (1.253-1.853)
6 / rs9271588 / 32590953 / C/T / T / 0.6880 / 0.5839 / 1.82×10-5 / 1.572 (1.279-1.931)
6 / rs9272627 / 32608060 / HLA-DQA1 / A/G / A / 0.3368 / 0.2285 / 2.07×10-7 / 1.714 (1.393-2.11)
6 / rs34965214 / 32609545 / HLA-DQA1 / T/C / C / 0.7769 / 0.6875 / 8.47×10-5 / 1.583 (1.26-1.988)
6 / rs35139945 / 32626267 / T/G / T / 0.3030 / 0.2136 / 1.77×10-5 / 1.6 (1.289-1.985)
6 / rs241429 / 32803840 / TAP2 / A/G / G / 0.5971 / 0.5017 / 9.88×10-5 / 1.472 (1.21-1.79)
6 / rs6938442 / 41469071 / T/C / T / 0.2169 / 0.1475 / 9.74×10-5 / 1.601 (1.26-2.034)
6 / rs664721 / 144599875 / G/A / A / 0.6446 / 0.5475 / 8.84×10-5 / 1.499 (1.227-1.831)
6 / rs586471 / 144600282 / C/T / T / 0.6446 / 0.5482 / 9.85×10-5 / 1.495 (1.224-1.826)
7 / rs117026326 / 74126034 / T/C / T / 0.2190 / 0.1040 / 6.71×10-13 / 2.417 (1.889-3.093)
8 / rs9297463 / 113114520 / C/T / C / 0.5764 / 0.4803 / 9.22×10-5 / 1.473 (1.212-1.789)
8 / rs10108081 / 113488660 / CSMD3 / A/G / G / 0.5711 / 0.4702 / 3.3×10-5 / 1.501 (1.234-1.825)
10 / rs7915172 / 1902922 / T/G / T / 0.5744 / 0.4778 / 7.62×10-5 / 1.475 (1.214-1.792)
10 / rs76164187 / 91928000 / A/G / A / 0.1494 / 0.0915 / 8.01×10-5 / 1.743 (1.316-2.307)
11 / rs76277332 / 21833646 / A/G / G / 0.8402 / 0.7561 / 5.56×10-5 / 1.697 (1.311-2.197)
11 / rs11026280 / 21850094 / T/C / C / 0.8430 / 0.7600 / 5.96×10-5 / 1.695 (1.308-2.198)
11 / rs75644662 / 21879248 / T/C / C / 0.8388 / 0.7540 / 4.81×10-5 / 1.698 (1.314-2.195)
11 / rs117768810 / 39013943 / C/T / C / 0.1612 / 0.0960 / 1.31×10-5 / 1.81 (1.378-2.376)
11 / rs76669520 / 39196942 / T/C / T / 0.1426 / 0.0865 / 7.52×10-5 / 1.757 (1.32-2.339)
11 / rs4128862 / 39439184 / T/G / T / 0.1219 / 0.0661 / 1.32×10-5 / 1.96 (1.439-2.671)
11 / rs76740328 / 131101502 / G/A / G / 0.1198 / 0.0651 / 1.83×10-5 / 1.955 (1.432-2.67)
12 / rs2239091 / 2601679 / CACNA1C / C/T / T / 0.5888 / 0.4875 / 3.5×10-5 / 1.506 (1.238-1.83)
12 / rs79345295 / 102942043 / T/G / T / 0.4835 / 0.3908 / 9.49×10-5 / 1.459 (1.202-1.77)
12 / rs11113415 / 108033488 / BTBD11 / C/T / C / 0.2087 / 0.1389 / 7.12×10-5 / 1.634 (1.281-2.084)
12 / rs7965597 / 108037966 / BTBD11 / A/G / A / 0.1860 / 0.1157 / 1.79×10-5 / 1.747 (1.352-2.256)
12 / rs2839722 / 108045751 / BTBD11 / G/A / G / 0.1983 / 0.1286 / 4.32×10-5 / 1.676 (1.307-2.149)
12 / rs1861588 / 108046493 / BTBD11 / G/C / G / 0.1992 / 0.1286 / 3.57×10-5 / 1.686 (1.315-2.162)
13 / rs41286108 / 75890728 / TBC1D4 / T/C / T / 0.1426 / 0.0843 / 6.78×10-5 / 1.806 (1.356-2.405)
13 / rs1373835 / 94094597 / GPC6 / A/G / A / 0.1178 / 0.0609 / 6.76×10-5 / 2.057 (1.5-2.82)
14 / rs1951054 / 26077408 / T/C / C / 0.7417 / 0.6522 / 9.11×10-5 / 1.531 (1.232-1.904)
15 / rs4906839 / 26273405 / LOC100128714 / G/A / G / 0.5455 / 0.4504 / 7.68×10-5 / 1.464 (1.207-1.777)
15 / rs11073401 / 86075156 / AKAP13 / T/C / T / 0.2355 / 0.1620 / 9.43×10-5 / 1.593 (1.263-2.009)
16 / rs17739271 / 80387019 / C/A / C / 0.2479 / 0.1691 / 3.6×10-5 / 1.62 (1.29-2.035)
16 / rs4782727 / 82301047 / C/A / C / 0.3533 / 0.2620 / 2.7×10-5 / 1.539 (1.255-1.887)
17 / rs9910950 / 64131710 / CEP112 / G/A / G / 0.1136 / 0.0634 / 5.34×10-5 / 1.895 (1.379-2.605)
17 / rs9905551 / 64164314 / CEP112 / C/A / C / 0.1529 / 0.0941 / 7.3×10-5 / 1.738 (1.317-2.294)
17 / rs12452188 / 64180398 / CEP112 / T/C / T / 0.1529 / 0.0943 / 8.23×10-5 / 1.733 (1.314-2.287)

Chr, chromosome; RAF controls, risk allele frequency in controls; RAF patients, risk allele frequency in patients; risk allele OR: risk-allele odds ratio; Trend P, P value derived from a one-degree-of-freedom of Armitage trend test. 95% CI: 95% confidence interval. SNPs failed assay design for Sequenom platform were highlighted in green; SNPs not reach 99% successful rate or not reach 99% concordance between Affymetrix and Sequenom platform were highlighted in pink; SNPs successfully analyzed in the replication collection were remained in white background.The continuous association SNPs of HLA region were marked in gray. The genes which SNPs are located on are listed.

Supplementary Table 4: SNPs with P < 10-4 in the GWAS collection and P <0.05 in the replication collection and results of joint analysis

Chr. / SNP / Position / Gene / Allele / Risk Allele / Stage / RAF Controls / RAF Patients / Trend P / Risk Allele OR
(95% CI)
1 / rs6671952 / 116220358 / VANGL1 / C/G / C / GWAS / 0.104 / 0.164 / 9.28×10-5 / 1.691 (1.292-2.213)
C / Replication / 0.110 / 0.076 / 0.04867 / 0.6678 (0.4448-1.003)
C / Joint / 0.107 / 0.127 / 0.08632 / 1.208 (0.9711-1.504)
1 / rs16845946 / 226623766 / C/T / C / GWAS / 0.058 / 0.108 / 3.25×10-5 / 1.973 (1.422-2.738)
T / Replication / 0.931 / 0.966 / 0.01222 / 2.097 (1.162-3.785)
T / Joint / 0.936 / 0.923 / 0.155 / 0.8201 (0.6235-1.079)
11 / rs117768810 / 39013943 / C/T / C / GWAS / 0.096 / 0.161 / 1.31×10-5 / 1.81 (1.378-2.376)
T / Replication / 0.890 / 0.932 / 0.01871 / 1.704 (1.111-2.614)
C / Joint / 0.104 / 0.122 / 0.1208 / 1.197 (0.9584-1.495)
12 / rs11113415 / 108033488 / BTBD11 / C/T / C / GWAS / 0.139 / 0.209 / 7.12×10-5 / 1.634 (1.281-2.084)
T / Replication / 0.847 / 0.904 / 0.004098 / 1.697 (1.178-2.445)
C / Joint / 0.147 / 0.161 / 0.2659 / 1.118 (0.9186-1.361)
12 / rs7965597 / 108037966 / BTBD11 / A/G / A / GWAS / 0.116 / 0.186 / 1.79×10-5 / 1.747 (1.352-2.256)
G / Replication / 0.867 / 0.910 / 0.02306 / 1.543 (1.059-2.247)
A / Joint / 0.125 / 0.146 / 0.09667 / 1.191 (0.9696-1.463)

Chr, chromosome; RAF controls, risk allele frequency in controls; RAF patients, risk allele frequency in patients; risk allele OR: risk-allele odds ratio; 95% CI: 95% confidence interval. Trend P, P value derived from a one-degree-of-freedom of Armitage trend test.The genes which SNPs are located on are listed.

Supplementary Table 5: SNPs with P < 10-4 in the GWAS collection and failed in replication (P0.05) in the replication collection and results of joint analysis

Chr. / SNP / Position / Gene / Allele / Risk Allele / Stage / RAF Controls / RAF Patients / Trend P / Risk Allele OR
(95% CI)
2 / rs72777025 / 9699010 / T/C / T / GWAS / 0.143 / 0.226 / 4.47×10-6 / 1.747 (1.378-2.215)
T / Replication / 0.151 / 0.184 / 0.1046 / 1.264 (0.951-1.68)
T / Joint / 0.148 / 0.208 / 5.74×10-6 / 1.518 (1.267-1.819)

Chr, chromosome; RAF controls, risk allele frequency in controls; RAF patients, risk allele frequency in patients; risk allele OR: risk-allele odds ratio; 95% CI: 95% confidence interval. Trend P, P value derived from a one-degree-of-freedom of Armitage trend test. The genes which SNPs are located on are listed.

Supplementary Figures

Supplementary Figure 1.Principal components analysis and quantile-quantile plot for the trend test

(a) The quantile-quantile (Q-Q) plot examination of P value distribution in GWAS. (b, c) We conduct principal components analysis (PCA) using EIGENSTRAT 2.0 with HapMap III data to correct our data for population stratification in GWAS. PCA was based on the genotype data of 40,000 SNPs, roughly equal spacing across the human genome and selected from high-quality SNPs in cases and controls.