Supplemental Table 1 Age and gender-specific cut-points used for MHO.

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Supplemental Table 1 Age and gender-specific cut-points used for MHO. Age SBP (mmhg) DBP (mmhg) HDL-C (mmol/l) TG (mmol/l) FG (mmol/l) Boys 6-11 90th * 90th * 1.03 1.24 5.6 12 121 76 1.13 1.44 5.6 13 123 78 1.1 1.48 5.6 14 125 79 1.07 1.52 5.6 15 126 81 1.04 1.56 5.6 16 128 82 1.03 1.59 5.6 17 128 83 1.03 1.62 5.6 18 129 84 1.03 1.65 5.6 Girls 6-11 90th * 90th * 1.03 1.24 5.6 12 121 80 1.25 1.6 5.6 13 123 82 1.25 1.53 5.6 14 125 83 1.26 1.46 5.6 15 126 84 1.26 1.44 5.6 16 128 84 1.27 1.46 5.6 17 128 85 1.27 1.53 5.6 18 129 85 1.28 1.61 5.6 19 130 85 1.29 1.68 5.6 20 130 85 1.3 1.7 5.6 SBP: systolic blood pressure; DBP: diastolic blood pressure; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; FG: fasting glucose * for age, sex and height

Supplemental Table 2 Agreement of MHO according to CR definition and IR definition IR definition CR definition MHO MUO Total MHO 181 148 329 MUO 270 614 884 Total 451 762 1213 Supplementary Table 1 described the proportion of each type of MHO and MUO divided from the CR definition within the IR definition. First, 14.9% of the overweight were classified as MHO and 50.6% as MUO by both definitions. Second, 40.1% of the subjects with MHO-IR were classified as MHO-CR. Of the subjects in the MUO-IR, 80.6% of them showed MUO-CR, whereas 19.4% were MHO-CR. Thus, the CR definition missed approximately two-thirds of the subjects who were considered as MHO by using the IR definition. In the other words, the IR definition missed above half of the subjects who were considered as MUO by using the CR definition. The k coefficient of agreement for the categorical data was 0.219 (P < 0.001), which also indicated a poor agreement between CR definition and IR definition.

Supplemental table 3 Prevalence of MHO in overweight and/or obesity under different definitions China BMI cut- point a CR1 CR2 IR1 IR2 MHO/obesity; n (%) 341/1213 329/1213 684/1213 451/1212 (28.1%) (27.1%) (56.4%) (37.2%) MHO/overweight and obesity; n 606/1855 605/1855 1142/1855 793/1855 (%) (32.7%) (32.6%) (61.6%) (42.7%) IOTF BMI cut- point b MHO/obesity; n (%) 182/777 174/777 393/777 249/777 (23.4%) (28.8%) (50.6%) (32.0%) MHO/overweight and obesity; 562/1778 560/1778 1079/1778 742/1778 n(%) (31.6%) (31.5%) (60.7%) (41.7%) CR: cardio-metabolic risk factors; IR: insulin resistance. CR1: A modified Adult Treatment Panel III cut-point for each component: SBP or DBP 90th percentile for age, sex and height; TG 1.24 mmol/l; HDL-C 1.03 mmol/l and FG 5.6 mmol/l; (MHO-CR: 0 risk factors; MUO-CR: 1 risk factors). CR2: The cut-points by Jolliffe et al were used to define CR factors for individuals 12 years old; while a criteria based on the modified ATP-III MS definition were applied for those aged below 12 years old. All details can be found in Supplemental Table 1. (MHO-CR: 0 risk factors; MUO-CR: 1 risk factors). IR1: MHO-CR: HOMA-IR 3.0; MUO-CR: HOMA-IR > 3.0 (which was the 95th percentile of our healthy reference children in BCAMS). IR2: MHO-CR: HOMA-IR 2.3; MUO-CR: HOMA-IR > 2.3 (which was the optimal point for diagnosis of metabolic syndrome in our previous study in BCAMS). a Overweight and obesity were defined by using the sex- and age-specific 85th and 95th percentile of BMI, respectively, recommended by the Working Group on Obesity in China. b Overweight and obesity were defined by using the sex- and age-specific 85th and 95th percentile of BMI, respectively, recommended by 2012-IOTF.

Supplemental table 4 Associations of the 22 candidate SNPs with MHO among children and adolescents SNP Gene a/a* MAF P(HWE) Allele(a/A) Genotype (aa/aa/aa) (%) P(logistic) Case Control Case Control Addictive Dominant Recessive MHO-CR BMI related rs1558902 FTO T/A 0.14 0.18 87.1/12.9 85.4/14.6 76.4/21.4/2.2 72.9/24.9/2.1 0.52 0.40 0.73 rs2237892 KCNQ1 T/C 0.31 0.10 36.4/63.7 30.0/70.0 11.9/48.9/39.2 9.3/41.4/49.3 0.005 0.27 0.003 rs2237897 KCNQ1 T/C 0.35 0.13 39.7/60.3 33.1/67.0 14.2/50.9/34.8 10.6/44.9/44.5 0.004 0.15 0.003 rs16858082 GNPDA2 C/T 0.38 0.19 65.5/34.5 60.4/39.7 42.3/46.4/11.3 37.2/46.3/16.5 0.024 0.09 0.043 rs2331841 MC4R A/G 0.26 0.62 76.1/24.0 72.2/28.0 56.5/39.1/4.4 53.0/38.3/8.8 0.07 0.28 0.022 rs4776970 MAP2K5 T/A 0.26 0.10 75.1/24.8 74.2/25.8 57.2/35.8/6.9 55.1/38.2/6.7 0.55 0.44 0.96 rs2030323 BNDF T/G 0.45 0.92 41.3/40.8 44.2/55.8 27.6/27.4/27.1 19.5/49.4/31.1 0.85 0.83 0.92 rs6545814 ADCY3/RBJ A/G 0.43 0.93 54.4/45.6 57.3/42.7 31.0/46.8/22.2 33.6/47.4/19.0 0.26 0.59 0.17 rs261967 PCSK1 A/C 0.45 0.99 52.9/47.2 54.4/45.7 28.2/49.4/22.5 28.0/52.7/19.3 0.36 0.85 0.17 rs652722 PAX6 T/C 0.35 0.86 33.2/66.8 35.5/64.7 10.4/45.6/44.0 13.1/44.7/42.3 0.43 0.23 0.77 rs12597579 GP2 T/C 0.28 0.67 28.0/72.0 27.0/73.1 6.9/42.1/50.9 8.4/37.1/54.5 0.71 0.33 0.31 rs516636 SEC16B C/A 0.24 0.55 77.5/22.6 76.1/24.0 58.4/38.2/3.5 58.0/36.1/5.9 0.61 0.98 0.14 rs2535633 ITIH4 C/G 0.44 0.48 55.3/44.6 55.4/44.6 33.4/43.8/22.7 31.8/47.2/21.0 0.97 0.53 0.52 rs11671664 GIPR/QPCTL A/G 0.50 1.38E-29 48.2/51.9 49.4/50.6 27.8/40.7/31.5 29.9/39.0/31.1 / / / Type 2 diabetes related rs2206734 CDKAL1 T/C 0.42 0.63 43.2/56.8 42.8/57.2 18.3/49.8/31.9 17.5/50.6/31.9 0.80 0.68 0.97 rs7903146 TCF7L2 C/T 0.04 0.85 96.2/3.8 95.6/4.4 92.4/7.6/0.0 91.6/8.0/0.4 0.80 0.92 / rs6769511 IGF2BP2 T/C 0.13 1.5E-193 86.9/13.1 87.2/12.8 80.4/12.9/6.6 81.8/10.7/7.4 / / / rs1801282 PPARG G/C 0.08 0.50 6.5/93.6 6.6/93.6 0.0/12.9/87.1 0.4/12.3/87.4 0.82 0.99 0.68 rs13266634 SLC30A8 T/C 0.44 2.87E-11 44.0/56.0 45.1/54.9 22.1/43.8/34.1 21.8/46.6/31.6 / / / Birth weight related rs1111875 HHEX/IDE C/T 0.28 0.60 71.0/29.1 72.1/28.1 49.1/43.7/7.2 51.6/40.9/7.6 0.71 0.55 0.81 rs9883204 ADCY5 T/C 0.004 0.82 0.3/99.7 0.2/99.8 0.0/0.6/99.4 0.0/0.4/99.6 0.68 / 0.68 rs1042725 HMGA2 C/T 0.21 0.22 78.7/21.2 79.0/20.9 61.9/33.6/4.4 62.8/32.4/4.7 0.55 0.52 0.89 MHO-IR BMI related rs1558902 FTO T/A 0.14 0.18 85.7/14.3 86.0/14.0 73.9/23.6/2.5 73.9/24.2/1.9 0.71 0.81 0.59 rs2237892 KCNQ1 T/C 0.31 0.10 35.4/64.7 29.6/70.3 13.4/43.9/42.7 8.0/43.2/48.7 0.009 0.004 0.09 rs2237897 KCNQ1 T/C 0.35 0.13 37.6/62.3 33.3/66.8 13.6/48.0/38.3 10.4/45.7/43.9 0.023 0.07 0.06

rs16858082 GNPDA2 C/T 0.38 0.19 62.6/37.5 61.3/38.7 39.1/46.9/14.0 38.3/46.0/15.7 0.72 0.99 0.49 rs2331841 MC4R A/G 0.26 0.62 74.6/25.5 72.4/27.6 55.8/37.5/6.7 52.9/39.0/8.1 0.24 0.37 0.28 rs4776970 MAP2K5 T/A 0.26 0.10 75.6/24.4 73.8/26.3 57.7/35.8/6.5 54.5/38.5/7.0 0.64 0.57 0.96 rs2030323 BNDF T/G 0.45 0.92 45.0/55.1 43.8/56.2 22.1/45.7/32.2 18.0/51.6/30.4 0.92 0.29 0.33 rs6545814 ADCY3/RBJ A/G 0.43 0.93 55.6/44.5 57.0/43.0 32.1/46.9/21.0 33.3/47.4/19.3 0.63 0.92 0.45 rs261967 PCSK1 A/C 0.45 0.99 52.5/47.4 54.8/45.2 27.1/50.8/22.0 28.6/52.4/19.0 0.30 0.47 0.33 rs652722 PAX6 T/C 0.35 0.86 35.1/64.9 34.6/65.3 9.8/50.6/39.6 13.8/41.6/44.5 0.43 0.26 0.08 rs12597579 GP2 T/C 0.28 0.67 26.9/73.1 27.4/72.7 7.4/39.0/53.6 8.3/38.1/53.6 0.54 0.34 0.80 rs516636 SEC16B C/A 0.24 0.55 77.2/22.8 76.0/24.0 59.9/34.6/5.5 57.1/37.8/5.1 0.85 0.74 0.21 rs2535633 ITIH4 C/G 0.44 0.48 56.8/43.2 54.5/45.6 35.3/43.0/21.7 30.4/48.2/21.5 0.14 0.04 0.87 rs11671664 GIPR/QPCTL A/G 0.50 1.38E-29 49.4/50.6 48.9/51.2 27.9/43.0/29.1 30.1/37.5/32.4 / / / Type 2 diabetes related rs2206734 CDKAL1 T/C 0.42 0.63 43.4/56.7 42.7/57.5 17.6/51.5/30.9 17.8/49.7/32.6 0.88 0.99 0.81 rs7903146 TCF7L2 C/T 0.04 0.85 96.1/3.9 95.6/4.4 92.4/7.4/0.2 91.5/8.2/0.3 0.78 0.91 0.99 rs6769511 IGF2BP2 T/C 0.13 1.5E-193 85.4/14.6 88.2/11.8 78.6/13.6/7.8 83.2/10.0/6.8 / / / rs1801282 PPARG G/C 0.08 0.50 6.8/93.2 6.3/93.7 0.2/13.1/86.6 0.3/12.0/87.7 0.61 0.92 0.59 rs13266634 SLC30A8 T/C 0.44 2.87E-11 47.2/53.0 43.4/56.6 24.2/45.9/30.0 20.5/45.8/33.7 / / / Birth weight related rs1111875 HHEX/IDE C/T 0.28 0.60 70.4/29.6 72.5/27.6 49.8/41.2/9.0 51.5/41.9/6.6 0.32 0.77 0.07 rs9883204 ADCY5 T/C 0.004 0.82 0.4/99.7 0.2/99.9 0.0/0.7/99.3 0.0/0.3/99.7 0.48 / 0.48 rs1042725 HMGA2 C/T 0.21 0.22 78.9/21.1 79.1/20.9 62.6/32.6/4.8 62.7/32.8/4.5 0.85 0.87 0.89 *a: non-effect; A: effect; minor allele frequency; P value for Hardy-Weinberg equilibrium test; P value for logistic regression adjusted for gender, age and Tanner stage in genotype. FTO, fat mass and obesity associated; KCNQ1, potassium channel, voltage gated KQT-like subfamily Q, member 1; GNPDA2, glucosamine-6-phosphate deaminase 2; MC4R, melanocortin 4 receptor; MAP2K5, mitogen-activated protein kinase 5; BNDF, brain-derived neurotrophic factor ; ADCY3/RBJ, adenylate cyclase 3; PCSK1, proprotein convertase subtilisin/kexin type 1; PAX6, paired box 6; GP2, glycoprotein 2; SEC16B, SEC16 homolog B, endoplasmic reticulum export factor; ITIH4, inter-alpha-trypsin inhibitor heavy chain family, member 4; GIPR/QPCTL, gastric inhibitory polypeptide receptor; CDKAL1, CDK5 (cyclin-dependent kinase 5 ) regulatory subunit associated protein 1-like 1; TCF7L2, transcription factor 7-like 2; IGF2BP2, insulin-like growth factor 2 mrna binding protein 2; PPARG, peroxisome proliferator-activated receptor gamma; SLC30A8, solute carrier family 30 (zinc transporter), member 8; HHEX/IDE, hematopoietically expressed homeobox/insulin-degrading enzyme; ADCY5, adenylate cyclase 5; HMGA2, high mobility group AT-hook 2. Boldface type indicates nominally significant values (P < 0.05)

1 2 3 4 5 6 7 8 9 Supplemental table 5 Associations of the 4 SNPs with the components of MHO among children and adolescents KCNQ1- rs2237892 KCNQ -rs2237897 GNPDA2-rs16858082 β P β P β P BMI z-score 0.055 0.037 0.043 0.102 0.046 0.080 WC z-score 0.08 0.015 0.07 0.032 0.045 0.145 FAT% z-score 0.017 0.689 0.021 0.624 0.113 0.005 SBP (mmhg) 0.318 0.522 0.092 0.851 1.235 0.009 DBP (mmhg) 0.501 0.207 0.75 0.056 0.601 0.11 TG (mmol/l) 0.093 0.001 0.062 0.022 0.01 0.692 HDL-C (mmol/l) -0.029 0.008-0.028 0.01-0.014 0.194 FG (mmol/l) 0.039 0.067 0.025 0.232 0.015 0.449 Ln-insulin* 0.068 0.012 0.043 0.103 0.034 0.189 Ln-HOMA-IR* 0.075 0.008 0.048 0.087 0.036 0.183 βmeans standardized coefficients, which was adjusted for gender, age and Tanner stage. BMI z-score: Body mass index z-score by CDC2000; WC z-score: Waist circumference z-score for per SD; FAT% z-score Fat mass percentage z-score for per SD; SBP: systolic blood pressure; DBP: diastolic blood pressure; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; FG: fasting glucose; HOMA-IR: homeostasis model assessment-insulin resistance index. * natural logarithm transformed. Boldface type indicates nominally significant values (P < 0.05). 6

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