Supplementary Table 1. Characteristics of the Study Subjects

Supplementary Table 1. Characteristics of the study subjects.

Gender / N / Age
(years; mean ± SD) / Height
(cm; mean ± SD)a
Normal individuals:
Stage 1 / Male / 740 / 50.2 ± 3.07 / 169.4 ± 5.67
Stage 2 / Male / 1,000 / 50.0 ± 4.91 / 169.3 ± 5.70
ISS patients: / Male / 64 / 8.86 ± 3.20 / -2.82 ± 0.54a
Female / 59 / 8.05 ± 2.32 / -2.69 ± 0.47a

a In the case of ISS patients, height-SDS is expressed instead of height (mean ± SD).

ISS, idiopathic short stature; SD, standard deviation; SDS, standard deviation score.
Supplementary Table 2. Previously reported height-associated loci/genes detected by GWA studies.

Gene / Cytomap / SNP ID / P-value / Reference
HSPG2 / 1p36.12 / rs3767141 / 3.50E-04 / [4]
CATSPER4 / 1p36.11 / rs11809207 / 6.1E-08 / [4]
SCMH1 / 1p34 / rs6686842 / 1.70E-08 / [2]
DAB1 / 1p32.2 / rs7533282 / 3.40E-04 / [4]
SPAG17 / 1p12 / rs12735613 / 4.40E-11 / [2]
rs17038182 / 4.7E-07 / [5]
SV2A / 1q12 / rs11205277 / 1.40E-10 / [1,10]
SF3B4 / 1q12 / rs11205277 / 1.40E-10 / [1,10]
DNM3 / 1q24 / rs678962 / 3.20E-08 / [1,10]
TSEN15 / 1q25 / rs2274432 / 7.80E-09 / [1,10]
ZNF678 / 1q42.13 / rs1390401 / 5.40E-09 / [2]
SH3BP5L / 1q44 / rs11205415 / 6.70E-08 / [10]
EFR3B / 2p23 / rs6733301 / 8.20E-07 / [1]
LTBP1 / 2p22.3 / rs41464348 / 7.40E-06 [5]
7.05E-06 [9] / [5,9]
SOCS5 / 2p21 / rs7596521 / 6.90E-05 / [4]
EFEMP1 / 2p16 / rs3791679 / 5.90E-11 / [1,10]
rs3791675 / 2.20E-12 [2]
1.70E-09 [5]
3.63E-06 [9] / [2,5,9]
NPAS2 / 2q11.2 / rs1542178 / 1.55E-04 / [12]
IHH / 2q33-q35 / rs1052483 / 1.20E-06 / [1]
rs6724465 / 2.10E-08 / [2]
NPPC / 2q37 / rs749052 / 1.40E-06 / [1]
DIS3L2 / 2q37-q37.1 / rs6717918 / 3.40E-09 / [6]
FLNB / 3p14 / rs9834312 / 7.30E-06 / [11]
CD86 / 3q21 / rs12106790 / 3.80E-08 / [10]
CEP63 / 3q22 / rs10935120 / 7.30E-08 / [2]
ZBTB38 / 3q23 / rs6440003 / 1.80E-24 [2]
5.37E-02 [9] / [2,9]
rs6763931 / 1.40E-27 [1]
3.10E-12 [4] / [1,4]
rs724016 / 8.30E-22 [3]
1.20E-06 [8] / [3,8]
rs10513137 / 5.60E-12 [5]
7.65E-08 [9] / [5,9]
LYAR / 4p16.3 / rs2916448 / 5.50E-04 / [3]
LCORL / 4p15.31 / rs6817306 / 3.3E-08 / [4]
rs16896068 / 2.40E-13 / [2]
rs6830062 / 1.30E-10 [1]
4.90E-09 [4] / [1,4,10]
PDGFRA / 4q12 / rs17690232 / 3.90E-07 / [8]
PRKG2 / 4q13.1-q21.1 / rs710841 / 1.90E-06 [1]
2.40E-08 [4] / [1,4]
rs2011962 / 6.2E-09 / [4]
rs1662845 / 9.10E-04 / [3]
HHIP / 4q28-q32 / rs1812175 / 9.70E-12 [1]
3.90E-06 [4] / [1,4,10]
rs6854783 / 2.10E-09 / [2,10]
rs1492820 / 1.20E-11 / [3]
WWC2 / 4q35.1 / rs955748 / 6.60E-05 / [4]
NPR3 / 5p13.3 / rs10472828 / 3.00E-07 [4]
3.40E-07 [6] / [4,6]
HOMER1 / 5q14.2 / rs10078095 / 3.10E-06 / [8]
LOC389328 / 5q31 / rs31198 / 8.20E-06 / [1]
RREB1 / 6p24.3 / rs2714357 / 5.10E-04 / [4]
BMP6 / 6p24 / rs12198986 / 2.40E-11 / [1,10]
DTNBP1 / 6p22.3 / rs742106 / 2.60E-04 / [4]
NUP153 / 6p22.3 / rs12199222 / 6.50E-06 / [1]
HIST1H1D / 6p21 / rs10946808 / 5.80E-10 [1]
3.80E-17 [3]
5.60E-12 [4] / [1,3,4,10]
HIST1H4F / 6p22.1 / rs9358913 / 6.8E-09 / [4]
BAT3 / 6p21 A / rs3130050 / 3.20E-08 / [1,10]
TNXB / 6p21 B / rs185819 / 3.20E-08 / [1,10]
NOTCH4 / 6p21.32 / rs3131296 / 1.80E-05 / [4]
HMGA1 / 6p21.31 / rs7742369 / 3.80E-08 / [4]
rs1776897 / 1.40E-08 [1]
7.80E-11 [4] / [1,4,10]
rs6918981 / 3.30E-08 [5]
2.07E-08 [9] / [5,9]
C6orf106 / 6p21.31 / rs2814993 / 4.10E-12 [2]
1.40E-10 [4] / [2,4]
PPARD / 6p21 E / rs4713858 / 3.50E-08 / [1,10]
SUPT3H / 6p21.1-p21.3 / rs10948197 / 7.55E-06 / [9]
rs9395066 / 7.50E-06 / [1]
LIN28B / 6q16.3-q21 / rs314277 / 1.10E-08 / [3,10]
rs314268 / 7.70E-07 / [1]
L3MBTL3 / 6q23 / rs6899976 / 1.10E-06 / [1]
GPR126 / 6q24.1 / rs6570507 / 4.4E-11 / [4]
rs4896582 / 2.40E-18 / [3]
rs3748069 / 4.50E-14 / [1,10]
GNA12 / 7p22.2 / rs798544 / 6.50E-15 / [1,10]
rs1182188 / 2.8E-09 / [4]
JAZF1 / 7p15.2-p15.1 / rs849141 / 3.2E-11 / [4]
rs1635852 / 9.40E-10 / [10]
GRB10 / 7p12.2 / rs12540874 / 2.70E-03 / [3]
CDK6 / 7q21-q22 / rs2040494 / 3.80E-07 / [3]
rs2282978 / 9.80E-09 [1]
7.80E-23 [2]
1.20E-08 [4] / [1,2,4,10]
WDR60 / 7q36.3 / rs2730245 / 3.00E-07 / [3]
AGPAT6 / 8p11.21 / rs11786297 / 3.90E-05 / [3]
PLAG1 / 8q12 / rs10958476 / 6.60E-08 / [1,10]
rs13273123 / 1.00E-09 [5]
3.05E-06 [9] / [5,9]
rs9650315 / 3.80E-07 / [3]
rs7815788 / 4.80E-06 / [4]
EXT1 / 8q24.11 / rs11989122 / 6.16E-07 / [9]
rs13251380 / 1.04E-04 / [12]
rs13249999 / 3.60E-04 / [3]
FREM1 / 9p22.3 / rs10961780 / 2.35E-06 / [9]
FBP2 / 9q22.3 / rs16910061 / 2.58E-06 / [9]
rs600130 / 9.90E-05 [5]
2.89E-06 [9] / [5,9]
PTCH1 / 9q22.3 / rs10512248 / 4.20E-11 [2]
3.00E-03 [12] / [2,12]
ZNF462 / 9q31 / rs4743034 / 2.10E-08 / [1,10]
COL27A1 / 9q32 / rs946053 / 1.20E-06 / [1]
PAPPA / 9q33.2 / rs7869550 / 1.20E-06 / [3]
FUBP3 / 9q34.11 / rs7466269 / 7.50E-07 / [3]
SH3PXD2A / 10q24.33 / rs7086883 / 3.40E-06 / [4]
ADRA2A / 10q24-q26 / rs11195417 / 8.16E-04 / [12]
SBF2 / 11p15.4 / rs10734652 / 2.70E-06 / [11]
ETV6 / 12p13 / rs2187642 / 3.50E-06 / [1]
PDE3A / 12p12 / rs11611208 / 2.20E-06 / [1]
HMGA2 / 12q14 / rs1480474 / 2.3E-11 / [4]
rs1042725 / 2.50E-18 [2]
2.70E-20 [3]
4.00E-16 [7] / [2,3,7]
rs8756 / 1.80E-16 [1]
5.00E-14 [4] / [1,4,10]
MYBPC1 / 12q23.2 / rs11110932 / 4.69E-02 / [12]
C12orf48 / 12q23.2 / rs2292303 / 8.08E-06 / [9]
GPR133 / 12q24.33 / rs1569019 / 1.02E-06 / [12]
RNF6 / 13q12.2 / rs10507349 / 3.64E-04 / [12]
LOC730194 / 13q14 / rs1239947 / 7.60E-06 / [1]
rs3118914 / 3.9E-10 / [4]
DPF3 / 14q24.2 / rs8009692 / 3.43E-02 / [6]
TMED10 / 14q24.3 / rs910316 / 1.4E-07 / [4]
TRIP11 / 14q24.3-32.2 / rs8007661 / 5.50E-10 / [3]
MARK3 / 14q32.3 / rs12894275 / 3.74E-05 / [6]
TMED3 / 15q24-q25 / rs11858942 / 1.50E-03 / [3]
SH3GL3 / 15q24-q25.2 / rs2562784 / 6.40E-08 / [3]
ADAMTSL3 / 15q25.2 / rs10906982 / 1.70E-08 / [2]
rs4842838 / 2.6E-08 / [4]
ACAN / 15q26.1 / rs8041863 / 8.10E-08 / [2]
ADAMTS17 / 15q26 / rs4533267 / 3.30E-08 / [1,10]
RAB40C / 16p13.3 / rs763014 / 5.10E-06 / [3]
NARFL / 16p13.3 / rs3752556 / 8.80E-06 / [4]
DNASE1L2 / 16p13.3 / rs26840 / 1.50E-04 / [3]
TXNL4B / 16q22.2 / rs152837 / 4.53E-04 / [12]
LOC440389 / 16q23.2 / rs11646174 / 9.93E-04 / [12]
CENTA2 / 17q1 / rs3760318 / 1.80E-09 / [1,10]
ANKFN1 / 17q22 / rs12449568 / 2.40E-06 / [3]
MAP3K3 / 17q23.3 / rs7209435 / 7.10E-07 / [1]
rs12325866 / 2.70E-06 / [4]
AFMID / 17q25.3 / rs16970909 / 7.36E-05 / [6]
CABLES1 / 18q11 / rs4800148 / 3.70E-09 / [1,10]
DYM / 18q12-q21.1 / rs8099594 / 3.10E-07 / [2]
DCC / 18q21.3 / rs12958987 / 4.50E-03 / [3]
DOT1L / 19p13.3 / rs12986413 / 2.90E-08 / [3]
ADAMTS10 / 19p13 / rs7249094 / 1.30E-06 / [1]
C20orf30 / 20p13 / rs6116651 / 4.70E-04 / [3]
UQCC / q11.22 / rs6060369 / 1.40E-16 [3]
9.73E-07 [8] / [3,8]
rs6088792 / 3.90E-06 [1]
1.50E-05 [8] / [1,8]
rs6060373 / 1.70E-17 [2]
1.18E-06 [8] / [2,8]
rs6088813 / 9.80E-14 [4]
2.27E-06 [8] / [4,8]
C20orf86 / 20q13.32 / rs4811971 / 5.82E-06 / [9]
BCR / 22q11 / rs5751614 / 6.40E-06 / [1]
TNRC6B / 22q13.1 / rs139909 / 1.78E-07 / [6]
IL17REL / 22q13.33 / rs137866 / 4.50E-04 / [12]

Total = 103 genes

Supplementary References

1. Gudbjartsson, D.F. et al. Many sequence variants affecting diversity of adult human height. Nat Genet 2008;40:609-615.

2. Weedon, MN. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 2008;40:575-583.

3. Lettre, G. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 2008;40:584-591.

4. Soranzo, N. et al. Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size. PLoS Genet 2009;5:e1000445.

5. Cho, YS. et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 2009;41:527-534.

6. Estrada, K. et al. A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation. Hum Mol Genet 2009;18:3516-3524.

7. Weedon MN. et al. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 2007;39:1245-1250.

8. Sanna S. et al. Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 2008;40:198-203.

9. Kim JJ. et al. Identification of 15 loci influencing height in a Korean population. J Hum Genet 2009;55:27-31.

10. Johansson A. et al. Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. Hum Mol Genet 2009;18:373-380.

11. Lei SF. et al. Genome-wide association study identifies two novel loci containing FLNB and SBF2 genes underlying stature variation. Hum Mol Genet 2009;18:1661-1669.

12. Tönjes A. et al. Genetic variation in GPR133 is associated with height: genome wide association study in the self-contained population of Sorbs. Hum Mol Genet 2009;18:4662-4668.

Supplementary Table 3.Average fold coverage and genetic variants (SNPs and Indels) identified by whole-exome sequencing in 12 individuals.

Sample / Total No. of reads / Total No. of bp / Average fold coverage / Total No. of SNPs / Total No. of Indels
1 / 68,974,872 / 5,104,140,528 / 135 / 25,058 / 1,816
2 / 71,812,502 / 5,314,125,148 / 141 / 24,162 / 1,342
3 / 66,689,634 / 4,935,032,916 / 131 / 25,247 / 1,895
4 / 70,595,870 / 5,224,094,380 / 138 / 24,201 / 1,289
5 / 59,195,308 / 4,498,843,408 / 119 / 23,828 / 1,175
6 / 62,827,376 / 4,774,880,576 / 126 / 23,367 / 1,088
7 / 63,111,154 / 4,796,447,704 / 127 / 24,123 / 1,229
8 / 64,953,892 / 4,936,495,792 / 131 / 23,404 / 1,332
9 / 67,467,936 / 4,992,627,264 / 132 / 24,073 / 1,335
10 / 67,536,338 / 4,997,689,012 / 132 / 24,096 / 1,254
11 / 62,742,746 / 4,768,448,696 / 126 / 23,894 / 1,313
12 / 63,415,552 / 4,819,581,952 / 127 / 23,497 / 1,134
Mean / 65,769,013 / 4,930,067,892 / 130 / 24,079 / 1,350

No, number; bp, base pairs; SNP, single-nucleotide polymorphism; Indels, insertions and deletions.

Average fold coverage was calculated as total number of base pairs/total base pairs of SureSelect.

Supplementary Table 4. Lists of candidate causal variants detected from exome sequencing data

Alleleb / Genotype (11/12/22) / MAF
SNP ID / Chr. / Positiona / 1 / 2 / Gene / ISS / Normal / ISS / Normal
Group 1: ISS-specific novel nsSNPs (2 out of 4 samples)
VPS13D-EK / 1 / 12243340 / A / G / VPS13D / 0/11/112 / 0/62/678 / 0.045 / 0.042
LAPTM5-TA / 1 / 31003119 / G / A / LAPTM5 / 0/13/110 / 2/90/648 / 0.053 / 0.064
FLG-GVc / 1 / 150551200 / A / C / FLG / N/A / N/A / N/A / N/A
REG3A-HPe / 2 / 79239331 / G / T / REG3A / 0/0/123 / 0/0/740 / 0 / 0
TUBA3D-YCe / 2 / 131956833 / G / A / TUBA3D / 0/0/123 / 0/0/740 / 0 / 0
ANKAR-KR / 2 / 190269305 / C / T / ANKAR / 0/6/117 / 0/32/708 / 0.024 / 0.022
DNAH7-EK / 2 / 196561132 / A / G / DNAH7 / 0/5/118 / 1/45/694 / 0.020 / 0.032
NFKBIZ-VGe / 3 / 103055325 / G / T / NFKBIZ / 0/0/123 / 0/0/740 / 0 / 0
KIAA0226-RQ / 3 / 198916397 / T / C / KIAA0226 / 0/11/112 / 1/61/678 / 0.045 / 0.0432
NCAPG-AT / 4 / 17428793 / A / G / NCAPG / 1/12/110 / 1/72/667 / 0.057 / 0.050
GDF9-DY / 5 / 132227956 / A / C / GDF9 / 0/13/110 / 4/58/678 / 0.053 / 0.045
BRD8-SFe / 5 / 137531638 / A / G / BRD8 / 0/0/123 / 0/0/740 / 0 / 0
GRM6-GS / 5 / 178342696 / T / C / GRM6 / 0/4/119 / 0/17/723 / 0.016 / 0.011
C6orf192-IV / 6 / 133146780 / C / T / C6orf192 / 0/4/119 / 0/13/727 / 0.016 / 0.009
FAM154A-R* / 9 / 18918508 / T / C / FAM154A / 0/5/118 / 0/18/722 / 0.020 / 0.012
ZNF782-SA / 9 / 98620655 / C / A / ZNF782 / 1/28/94 / 5/130/605 / 0.122 / 0.095
SLC27A4-RH / 9 / 130147500 / T / C / SLC27A4 / 0/8/115 / 0/8/732 / 0.033 / 0.005
NHLRC2-IV / 10 / 115658139 / G / A / NHLRC2 / 0/16/107 / 1/53/686 / 0.065 / 0.037
PPFIBP2-MTd / 11 / 7629605 / C / T / PPFIBP2 / N/A / N/A / N/A / N/A
NUMA1-LV / 11 / 71406470 / C / G / NUMA1 / 0/5/118 / 0/47/693 / 0.020 / 0.032
SIAE-GS / 11 / 124044505 / A / G / SIAE / 2/30/91 / 17/162/561 / 0.138 / 0.132
DDX11-APc / 12 / 31142142 / C / G / DDX11 / N/A / N/A / N/A / N/A
MIP-VI-1d / 12 / 55134346 / T / C / MIP / N/A / N/A / N/A / N/A
MIP-VI-2 / 12 / 55134466 / A / G / MIP / 0/5/118 / 0/7/733 / 0.020 / 0.005
ANKLE2-EK / 12 / 131816783 / A / G / ANKLE2 / 2/35/86 / 17/165/558 / 0.159 / 0.134
NUDT15-RC / 13 / 47517856 / T / C / NUDT15 / 4/23/96 / 15/149/576 / 0.126 / 0.121
LRRC49-QL / 15 / 69063536 / T / A / LRRC49 / 18/48/57 / 118/337/285 / 0.342 / 0.387
CHRNB1-MT / 17 / 7300654 / C / T / CHRNB1 / 0/4/119 / 1/41/698 / 0.016 / 0.029
CDC27-CSe / 17 / 42569563 / A / T / CDC27 / 0/0/123 / 0/0/740 / 0 / 0
CDC27-VGe / 17 / 42571159 / C / A / CDC27 / 0/0/123 / 0/0/740 / 0 / 0
EVPL-RSe / 17 / 71529149 / T / G / EVPL / 0/0/123 / 0/0/740 / 0 / 0
NPHS1-VL / 19 / 41022296 / G / C / NPHS1 / 0/4/119 / 1/22/717 / 0.016 / 0.016
ZNF565-GV / 19 / 41366373 / A / C / ZNF565 / 1/17/105 / 5/105/630 / 0.077 / 0.078
NINL-SL / 20 / 25405690 / A / G / NINL / 0/14/109 / 3/76/661 / 0.057 / 0.055
SNAP29-SG / 22 / 19565389 / G / A / SNAP29 / 0/16/107 / 3/71/666 / 0.065 / 0.052
CHEK2-KEc / 22 / 27421840 / C / T / CHEK2 / N/A / N/A / N/A / N/A
CXorf59-LV / X / 36072605 / C / G / CXorf59 / 15/29/79 / 216/0/523 / 0.253 / 0.292
MAGEC1-RP / X / 140821467 / C / G / MAGEC1 / 0/0/123 / 6/0/734 / 0.000 / 0.008
Group 2: ISS-specific known nsSNPs (2 or 3 out of 4 samples) + functions
rs28581776 / 1 / 1837839 / C / T / CALML6 / 1/31/91 / 14/191/535 / 0.134 / 0.148
rs897471 / 1 / 22064041 / C / T / HSPG2 / 3/23/97 / 7/138/595 / 0.118 / 0.103
rs2147914 / 1 / 39124858 / T / G / RHBDL2 / 11/43/69 / 52/273/415 / 0.264 / 0.255
rs2070123 / 1 / 78888493 / G / A / IFI44 / 0/34/89 / 7/177/556 / 0.138 / 0.129
rs2230194 / 1 / 154547595 / A / G / CCT3 / 7/51/65 / 38/288/414 / 0.264 / 0.246
rs360057 / 1 / 224141186 / C / A / LEFTY1 / 3/49/71 / 23/248/469 / 0.224 / 0.199
rs7570797 / 2 / 68726575 / C / T / PROKR1 / 0/6/117 / 0/42/698 / 0.024 / 0.028
rs2066518 / 2 / 216996633 / C / G / SMARCAL1 / 2/38/83 / 26/188/526 / 0.171 / 0.162
rs16858780 / 3 / 185586597 / C / A / CHRD / 12/64/47 / 84/346/310 / 0.358 / 0.347
rs3208941 / 4 / 140407544 / A / G / C4orf49 / 0/22/101 / 3/108/629 / 0.089 / 0.077
rs10044879 / 5 / 150909127 / T / C / FAT2 / 0/7/116 / 0/40/700 / 0.028 / 0.027
rs9386806 / 6 / 109870915 / T / C / SMPD2 / 0/5/118 / 1/32/707 / 0.020 / 0.023
rs3212298 / 7 / 130844279 / T / C / PODXL / 10/46/67 / 45/255/440 / 0.268 / 0.233
rs3752368 / 7 / 157623852 / A / G / PTPRN2 / 0/15/108 / 4/92/644 / 0.061 / 0.068
rs35022521 / 8 / 1987835 / A / C / MYOM2 / 3/34/86 / 8/175/557 / 0.163 / 0.129
rs12674488 / 8 / 6325714 / T / G / MCPH1 / 4/26/93 / 16/195/529 / 0.138 / 0.153
rs11136343 / 8 / 145130974 / C / T / PARP10 / 1/26/96 / 8/159/573 / 0.114 / 0.118
rs2296212 / 9 / 2181309 / C / G / SMARCA2 / 9/40/74 / 37/228/475 / 0.236 / 0.204
rs3780548 / 9 / 98565308 / G / A / ZNF510 / 1/28/94 / 5/127/608 / 0.122 / 0.093
rs10817479 / 9 / 115125244 / A / G / WDR31 / 2/37/84 / 29/202/509 / 0.167 / 0.176
rs11196389 / 10 / 115341995 / G / A / NRAP / 0/22/101 / 7/128/605 / 0.089 / 0.096
rs2234279 / 11 / 2381117 / G / C / TSSC4 / 1/29/93 / 10/180/550 / 0.126 / 0.135
rs3794084 / 11 / 12214365 / G / C / MICAL2 / 0/17/106 / 2/90/648 / 0.069 / 0.064
rs12272419 / 11 / 28066727 / C / T / KIF18A / 13/54/56 / 80/321/339 / 0.325 / 0.325
rs3736228 / 11 / 67957871 / T / C / LRP5 / 8/59/56 / 50/271/419 / 0.305 / 0.251
rs7950873 / 11 / 77090499 / C / T / RSF1 / 2/14/107 / 4/77/659 / 0.073 / 0.057
rs2075033 / 12 / 514598 / A / G / B4GALNT3 / 5/34/84 / 26/185/529 / 0.179 / 0.160
rs10963 / 12 / 7172584 / A / G / RBP5 / 29/51/43 / 140/372/228 / 0.443 / 0.441
rs5744751 / 12 / 131764068 / A / G / POLE / 2/29/92 / 14/167/559 / 0.134 / 0.132
rs3744921 / 18 / 28121686 / G / A / FAM59A / 1/13/109 / 6/99/635 / 0.061 / 0.075
rs1113265 / X / 79585249 / C / G / FAM46D / 6/8/109 / 38/0/701 / 0.082 / 0.051
Group 3: ISS-specific nsSNPs from GWAS
rs12133381 / 1 / 118459475 / A / G / SPAG17 / 4/46/73 / 37/264/439 / 0.220 / 0.228
SV2A-EK / 1 / 148144937 / A / G / SV2A / 0/2/121 / 0/1/739 / 0.008 / 0.001
DIS3L2-RQ / 2 / 232836183 / T / C / DIS3L2 / 0/5/118 / 0/24/716 / 0.020 / 0.016
rs13096789 / 3 / 67137339 / G / A / KBTBD8 / 0/12/111 / 2/40/698 / 0.049 / 0.030
rs1127826 / 3 / 135760960 / G / A / CEP63 / 18/51/54 / 83/342/315 / 0.354 / 0.343
rs62282002 / 3 / 142644818 / C / G / ZBTB38 / 8/55/60 / 62/290/388 / 0.289 / 0.280
rs16851435 / 3 / 142644875 / G / T / ZBTB38 / 12/58/53 / 95/323/322 / 0.333 / 0.347
rs35597368 / 4 / 54834528 / G / A / PDGFRA / 1/24/98 / 12/171/557 / 0.106 / 0.132
RREB1-PR / 6 / 7175781 / G / C / RREB1 / 0/2/121 / 0/6/734 / 0.008 / 0.004
rs35742417 / 6 / 7192343 / T / G / RREB1 / 0/6/117 / 0/30/710 / 0.024 / 0.020
NOTCH4-RH / 6 / 32276672 / T / C / NOTCH4 / 0/2/121 / 0/10/730 / 0.008 / 0.007
rs2071282 / 6 / 32296921 / A / G / NOTCH4 / 0/14/109 / 2/102/636 / 0.057 / 0.072
GRB10-YH / 7 / 50767468 / G / A / GRB10 / 0/1/122 / 1/15/724 / 0.004 / 0.011
rs357564 / 9 / 97249415 / C / T / PTCH1 / 24/64/35 / 178/359/203 / 0.455 / 0.483
SH3PXD2A-AV / 10 / 105362686 / T / C / SH3PXD2A / 3/31/89 / 11/159/570 / 0.150 / 0.122
GPR133-AV / 12 / 130064702 / A / G / GPR133 / 0/2/121 / 0/4/736 / 0.008 / 0.003
rs2273183 / 14 / 91524395 / G / T / TRIP11 / 0/2/121 / 0/19/721 / 0.008 / 0.013
TRIP11-EK / 14 / 91529980 / T / C / TRIP11 / 2/14/107 / 4/138/598 / 0.073 / 0.099
rs59635749 / 14 / 91542169 / G / C / TRIP11 / 2/14/107 / 4/138/598 / 0.073 / 0.099
rs2277848 / 15 / 82430313 / A / G / ADAMTSL3 / 1/2/120 / 1/41/698 / 0.016 / 0.029
ACAN-PT / 15 / 87184345 / T / G / ACAN / 0/1/122 / 0/11/729 / 0.004 / 0.007
rs2882676 / 15 / 87201093 / T / G / ACAN / 4/37/82 / 24/200/516 / 0.183 / 0.168
rs2573652 / 15 / 98332137 / T / C / ADAMTS17 / 29/63/31 / 168/343/229 / 0.492 / 0.459
AFMID-AP / 17 / 73698703 / C / G / AFMID / 1/25/97 / 11/151/578 / 0.110 / 0.117
rs12484731 / 22 / 21957238 / T / G / BCR / 0/2/121 / 0/24/716 / 0.008 / 0.016
rs35537221 / 22 / 21962547 / G / A / BCR / 0/2/121 / 1/27/712 / 0.008 / 0.020
Group 4: Indels
RWDD3 / 1 / 95484973 / + / -AAG / RWDD3 / 0/6/122 / 0/1/139 / 0.02 / 0.004
GEN1 / 2 / 17826475 / + / -AAGTT / GEN1 / 1/11/36 / 0/12/60 / 0.14 / 0.08
BARD1 / 2 / 215353748 / + / -TGGTGAAGAACATTCAGGCAA / BARD1 / 1/17/110 / 0/13/126 / 0.07 / 0.05
MYST3 / 8 / 41913954 / + / -TCT / MYST3 / 0/7/41 / 0/6/66 / 0.07 / 0.04

SNP, single nucleotide polymorphism; ISS, idiopathic short stature; MAF, minor allele frequency; GWAS, genome-wide association study; NA, not available.

a Chromosome positions are based on NCBI build 36.

b Allele 1 refers to a minor allele.

c Assay design failed

d Poor clustering

e Monomorphic

Supplementary Table 5. Association results for 11 SNPs genotyped in the replication study of height in normal individuals

Allelec / Allelic / Additive / Dominant / Recessive / Genotype / Height (meanSD)
SNP / Chr. / Positiona / Geneb / AA change / PolyPhen prediction / 1 / 2 / MAF / BETA / SE / P / BETA / SE / P / BETA / SE / P / BETA / SE / P / 11/12/22 / 11 / 12 / 22
Stage 1
Novel / 2 / 232836183 / DIS3L2 / R483Q / possibly damaging / T / C / 0.016 / -2.53 / 1.17 / 0.032 / -2.56 / 1.16 / 0.028 / -2.56 / 1.16 / 0.028 / NA / NA / NA / 0/24/716 / NA / 166. 6.19 / 169.55.64
rs62282002 / 3 / 142644818 / ZBTB38 / P300A / probably damaging / C / G / 0.280 / 0.56 / 0.32 / 0.085 / 0.49 / 0.32 / 0.127 / 0.09 / 0.41 / 0.823 / 2.34 / 0.74 / 0.002 / 62/290/388 / 171.65.95 / 169.05.97 / 169.35.32
rs16851435 / 3 / 142644875 / ZBTB38 / S319A / benign / G / T / 0.347 / 0.42 / 0.30 / 0.165 / 0.38 / 0.3 / 0.203 / -0.04 / 0.42 / 0.924 / 1.70 / 0.61 / 0.006 / 95/323/322 / 170.95.78 / 168.95.96 / 169.45.26
Novel / 9 / 18918508 / FAM154A / R323* / probably damaging / T / C / 0.012 / 2.66 / 1.35 / 0.049 / 2.60 / 1.33 / 0.052 / 2.60 / 1.33 / 0.052 / NA / NA / NA / 0/18/722 / NA / 172.04.64 / 169.35.68
rs357564 / 9 / 97249415 / PTCH1 / P1315L / probably damaging / C / T / 0.483 / -0.58 / 0.29 / 0.047 / -0.48 / 0.29 / 0.098 / -0.61 / 0.46 / 0.187 / -0.67 / 0.48 / 0.165 / 178/359/203 / 168.75.73 / 169.45.59 / 169.95.73
rs2234279 / 11 / 2381117 / TSSC4 / H226Q / possibly damaging / G / C / 0.135 / -0.88 / 0.44 / 0.045 / -0.83 / 0.43 / 0.056 / -0.87 / 0.47 / 0.064 / -1.46 / 1.78 / 0.413 / 10/180/550 / 167.88.06 / 168.75.51 / 169.65.66
rs12272419 / 11 / 28066727 / KIF18A / T273A / benign / C / T / 0.325 / 0.20 / 0.31 / 0.532 / 0.25 / 0.31 / 0.422 / -0.19 / 0.41 / 0.641 / 1.64 / 0.66 / 0.013 / 80/321/339 / 170.95.84 / 168.85.72 / 169.55.51
Novel / 12 / 130064702 / GPR133 / A446V / benign / A / G / 0.003 / 5.96 / 2.84 / 0.036 / 5.82 / 2.8 / 0.038 / 5.82 / 2.8 / 0.038 / NA / NA / NA / 0/4/736 / NA / 175.34.04 / 169.35.66
Novel / 15 / 87184345 / ACAN / P185T / possibly damaging / T / G / 0.007 / -4.47 / 1.72 / 0.009 / -4.51 / 1.69 / 0.008 / -4.51 / 1.69 / 0.008 / NA / NA / NA / 0/11/729 / NA / 165.04.92 / 169.45.66
rs3744921 / 18 / 28121686 / FAM59A / K291R / benign / G / A / 0.075 / 1.25 / 0.55 / 0.022 / 1.23 / 0.54 / 0.024 / 1.36 / 0.59 / 0.021 / 1.34 / 2.30 / 0.56 / 6/99/635 / 170.54.60 / 170.65.78 / 169.25.64
Novel / 20 / 25405690 / NINL / S746L / benign / A / G / 0.055 / -1.47 / 0.64 / 0.021 / -1.41 / 0.63 / 0.025 / -1.52 / 0.67 / 0.023 / -1.38 / 3.24 / 0.671 / 3/76/661 / 168.28.85 / 167.95.27 / 169.55.69
Replication
Novel / 2 / 232836183 / DIS3L2 / R483Q / possibly damaging / T / C / 0.015 / 0.33 / 1.06 / 0.756 / 0.30 / 1.04 / 0.771 / 0.30 / 1.04 / 0.771 / NA / NA / NA / 0/30/957 / NA / 169.6±6.44 / 169.3±5.69
rs62282002 / 3 / 142644818 / ZBTB38 / P300A / probably damaging / C / G / 0.301 / 0.30 / 0.28 / 0.293 / 0.40 / 0.28 / 0.148 / 0.38 / 0.36 / 0.289 / 0.89 / 0.62 / 0.1553 / 89/403/473 / 169.8±5.70 / 169.3±5.70 / 169.1±5.68
Novel / 9 / 18918508 / FAM154A / R323* / probably damaging / T / C / 0.025 / 2.25 / 1.16 / 0.051 / 2.01 / 1.14 / 0.078 / 2.01 / 1.14 / 0.078 / NA / NA / NA / 0/25/962 / NA / 171.5±6.81 / 169.3±5.67
rs357564 / 9 / 97249415 / PTCH1 / P1315L / probably damaging / C / T / 0.468 / 0.11 / 0.26 / 0.676 / 0.14 / 0.26 / 0.592 / 0.00 / 0.40 / 0.991 / 0.39 / 0.44 / 0.3674 / 212/491/274 / 169.6±5.60 / 169.1±5.74 / 169.4±5.76
rs2234279 / 11 / 2381117 / TSSC4 / H226Q / possibly damaging / G / C / 0.135 / -0.80 / 0.38 / 0.038 / -0.72 / 0.38 / 0.056 / -0.79 / 0.41 / 0.055 / -0.87 / 1.57 / 0.5797 / 13/240/732 / 169±4.51 / 168.6±5.56 / 169.6±5.77
rs12272419 / 11 / 28066727 / KIF18A / T273A / benign / C / T / 0.339 / 0.60 / 0.27 / 0.029 / 0.54 / 0.27 / 0.044 / 0.43 / 0.36 / 0.23 / 1.33 / 0.56 / 0.0186 / 112/443/430 / 170.6±5.71 / 169.3±5.84 / 169±5.56
Novel / 12 / 130064702 / GPR133 / A446V / benign / A / G / 0.001 / -2.53 / 4.05 / 0.532 / -2.21 / 3.98 / 0.578 / -2.21 / 3.98 / 0.578 / NA / NA / NA / 0/2/985 / NA / 166.8±0.28 / 169.3±5.72
Novel / 15 / 87184345 / ACAN / P185T / possibly damaging / T / G / 0.003 / 2.09 / 2.34 / 0.372 / 2.12 / 2.30 / 0.357 / 2.12 / 2.30 / 0.357 / NA / NA / NA / 0/6/981 / NA / 171.4±3.31 / 169.3±5.72
rs3744921 / 18 / 28121686 / FAM59A / K291R / benign / G / A / 0.072 / 0.76 / 0.49 / 0.12 / 0.72 / 0.48 / 0.135 / 0.80 / 0.52 / 0.122 / 0.55 / 2.12 / 0.7958 / 7/127/850 / 170.1±6.44 / 170±5.52 / 169.2±5.69
Novel / 20 / 25405690 / NINL / S746L / benign / A / G / 0.056 / 0.33 / 0.57 / 0.56 / 0.23 / 0.56 / 0.679 / 0.23 / 0.58 / 0.697 / 0.77 / 3.26 / 0.8138 / 3/102/860 / 169.2±6.25 / 169.7±5.54 / 169.3±5.74
Combined
Novel / 2 / 232836183 / DIS3L2 / R483Q / possibly damaging / T / C / 0.016 / -0.94 / 0.79 / 0.234 / -0.96 / 0.78 / 0.215 / -0.96 / 0.78 / 0.215 / NA / NA / NA / 0/54/1673 / NA / 168.4±6.42 / 169.4±5.67
rs62282002 / 3 / 142644818 / ZBTB38 / P300A / probably damaging / C / G / 0.292 / 0.40 / 0.21 / 0.057 / 0.44 / 0.21 / 0.033 / 0.26 / 0.27 / 0.331 / 1.50 / 0.48 / 0.0017 / 151/693/861 / 170.5±5.85 / 169.2±5.81 / 169.2±5.52
Novel / 9 / 18918508 / FAM154A / R323* / probably damaging / T / C / 0.012 / 2.42 / 0.88 / 0.006 / 2.25 / 0.87 / 0.01 / 2.25 / 0.87 / 0.01 / NA / NA / NA / 0/43/1684 / NA / 171.7±5.94 / 169.3±5.68
rs357564 / 9 / 97249415 / PTCH1 / P1315L / probably damaging / C / T / 0.475 / -0.19 / 0.19 / 0.319 / -0.14 / 0.19 / 0.466 / -0.26 / 0.30 / 0.387 / -0.10 / 0.32 / 0.7579 / 390/850/477 / 169.2±5.67 / 169.3±5.67 / 169.6±5.75
rs2234279 / 11 / 2381117 / TSSC4 / H226Q / possibly damaging / G / C / 0.135 / -0.83 / 0.29 / 0.004 / -0.77 / 0.29 / 0.007 / -0.82 / 0.31 / 0.008 / -1.17 / 1.18 / 0.3214 / 23/420/1282 / 168.4±6.17 / 168.7±5.53 / 169.6±5.72
rs12272419 / 11 / 28066727 / KIF18A / T273A / benign / C / T / 0.333 / 0.42 / 0.21 / 0.039 / 0.41 / 0.20 / 0.045 / 0.15 / 0.27 / 0.59 / 1.46 / 0.43 / 0.0007 / 192/764/769 / 170.7±5.75 / 169.1±5.79 / 169.3±5.54
Novel / 12 / 130064702 / GPR133 / A446V / benign / A / G / 0.002 / 3.13 / 2.33 / 0.179 / 3.19 / 2.29 / 0.165 / 3.19 / 2.29 / 0.165 / NA / NA / NA / 0/6/1721 / NA / 172.5±5.39 / 169.3±5.69
Novel / 15 / 87184345 / ACAN / P185T / possibly damaging / T / G / 0.005 / -2.13 / 1.39 / 0.126 / -2.12 / 1.37 / 0.121 / -2.12 / 1.37 / 0.121 / NA / NA / NA / 0/17/1710 / NA / 167.2±5.35 / 169.4±5.69
rs3744921 / 18 / 28121686 / FAM59A / K291R / benign / G / A / 0.073 / 0.98 / 0.36 / 0.007 / 0.95 / 0.36 / 0.009 / 1.05 / 0.39 / 0.007 / 0.89 / 1.56 / 0.5693 / 13/226/1485 / 170.3±5.44 / 170.3±5.63 / 169.2±5.67
Novel / 20 / 25405690 / NINL / S746L / benign / A / G / 0.056 / -0.45 / 0.42 / 0.284 / -0.50 / 0.42 / 0.234 / -0.54 / 0.44 / 0.219 / -0.23 / 2.30 / 0.9188 / 6/178/1521 / 168.7±6.87 / 168.9±5.48 / 169.4±5.71

SNP, single-nucleotide polymorphism; AA, amino acid; MAF, minor allele frequency; SE, standard error; SD, standard deviation; NA, not available.

A linear regression analysis adjusted for age was used. Significant values are shown in bold.

a Chromosome positions are based on NCBI build 36.

b Loci selected from previous GWA studies are underlined.

c Allele 1 refers to a minor allele.

Supplementary Table 6. List of nonsynonymous SNPs significantly associated with ISS.

Alleleb / MAF / Allelic / Additive / Dominant / Recessive
SNP / Chr. / Positiona / Gene / AA change / PolyPhen prediction / 1 / 2 / ISS / Control / OR / 95% CI / P / OR / 95% CI / P / OR / 95% CI / P / OR / 95% CI / P
Novel / 9 / 130147500 / SLC27A4 / R136H / benign / T / C / 0.033 / 0.006 / 5.85 / 2.17-15.73 / 0.00097 / 8.95 / 3.00-26.66 / 8.36E-05 / 8.95 / 3.00-26.66 / 8.36E-05 / NA / NA / NA
Novel / 10 / 115658139 / NHLRC2 / I679V / benign / G / A / 0.065 / 0.037 / 1.80 / 1.01-3.21 / 0.043 / 2.74 / 1.40-5.37 / 0.00321 / 2.94 / 1.47-5.85 / 0.002193 / NA / NA / 0.999
Novel / 12 / 55134466 / MIP / V67I / benign / A / G / 0.020 / 0.005 / 4.13 / 1.30-13.11 / 0.023 / 3.19 / 0.65-15.70 / 0.1531 / 3.19 / 0.65-15.70 / 0.1531 / NA / NA / NA

SNP, single-nucleotide polymorphism; AA, amino acid; ISS, idiopathic short stature; MAF, minor allele frequency; OR, odds ratio; 95% CI, 95% confidence interval; NA, not available.

2-tests and logistic regression analyses adjusted for sex were used. Significant values are shown in bold.

a Chromosome positions are based on NCBI build 36.

b Allele 1 refers to a minor allele.

Supplementary Table 7. Genotype frequencies of the R136H variant in the SLC27A4 gene by the population

Genotype (CC/CT/TT)
Population / ISS / Control
Korean / 115/8/0 / 732/8/0
Japanese / 127/0/0 / 181/4/0
Spanish / NA / 188/0/0

ISS, idiopathic short stature; NA, not available