Table 3.
High-dimensional mediation analysis for the association of BMI z-score in mid-childhood with cardio-metabolic risk score in early adolescence via DNA methylation in mid-childhood (Results of CpG sites selected by sure independence screening criterion and a variable selection technique (minimax concave penalty)).
| Joint significance testa |
Leave-one-out cross-validationb |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| CpG | chr | αc | βd | FDR | % TEe | mean αc | mean βd | Gene symbol | Gene region | Relation to Island |
| cg03205258 | 22 | 0.06 | 0.14 | 0.53 | 2.45% | 0.06 | 0.13 | TXNRD2;COMT | 1stExon;1stExon;5ʹUTR | Island |
| cg01832325 | 11 | 0.04 | 0.15 | 0.53 | 2.11% | NA | NA | HBBP1 | TSS1500 | OpenSea |
| cg25825612 | 17 | −0.04 | −0.17 | 0.53 | 1.95% | −0.04 | −0.14 | TBCD | Body | N_Shelf |
| cg04967734 | 11 | −0.03 | −0.17 | 0.53 | 1.85% | −0.03 | −0.12 | DDX10 | Body | OpenSea |
| cg22683879 | 19 | 0.05 | 0.09 | 0.53 | 1.50% | 0.05 | 0.09 | MIR1181;CDC37 | TSS200;TSS200 | Island |
| cg14732969 | 3 | −0.06 | −0.03 | 0.53 | 0.55% | NA | NA | S_Shore | ||
| cg08033383 | 1 | 0.01 | 0.06 | 0.53 | 0.24% | NA | NA | FAM40A | 1stExon | Island |
| cg08189124 | 11 | 0.03 | 0.25 | 0.54 | 2.17% | NA | NA | N_Shelf | ||
| cg06897686 | 2 | 0.01 | 0.33 | 0.67 | 1.22% | 0.01 | 0.3 | ATOH8 | Body | Island |
| cg24780236 | 7 | −0.02 | −0.2 | 0.67 | 1.14% | −0.02 | −0.19 | TAS2R40 | TSS1500 | OpenSea |
| cg05677579 | 3 | 0.01 | 0.11 | 0.67 | 0.36% | NA | NA | RRP9;PARP3 | TSS1500;TSS200 | Island |
| cg23081542 | 7 | −3.17E-03 | −0.18 | 0.83 | 0.19% | NA | NA | LOC723809 | Body | OpenSea |
| cg01025283 | 3 | −0.05 | 0.15 | 0.23 | −2.25% | −0.05 | 0.16 | FAIM | TSS200;5ʹUTR;1stExon | Island |
| cg26494138 | 2 | −0.05 | 0.24 | 0.23 | −4.18% | −0.05 | 0.20 | S_Shore | ||
| cg23992886 | 7 | 0.02 | −0.14 | 0.54 | −0.89% | NA | NA | MET;MET | Body;Body | OpenSea |
| cg07026904 | 11 | −0.02 | 0.06 | 0.67 | −0.42% | NA | NA | S_Shore | ||
| cg23331961 | 15 | 0.02 | −0.13 | 0.67 | −0.67% | 0.02 | −0.12 | PARP6 | TSS1500 | N_Shore |
| cg11631158 | 13 | 0.01 | −0.09 | 0.76 | −0.43% | 0.01 | −0.09 | SHISA2 | Body | N_Shore |
| cg18647237 | 5 | 4.50E-04 | −0.26 | 0.98 | −0.04% | 4.35E-04 | −0.20 | N_Shore | ||
Abbreviation: false discovery rate (FDR); Body mass index (BMI); BMI z-score (BMIz); DNA methylation (DNAm); the proportion of total effect (% TE)
a In the joint significance test, FDR of the BMIz – DNAm associations (α) and FDR of the DNAm – cardio-metabolic risk score associations (β) were estimated separately, and the larger FDR was reported;
b In the leave-one-out cross-validation, 265 validation tests were performed by excluding one participant from the full dataset. Only the CpGs being selected by the variable selection procedure in more than 95% of the validation tests were reported in this study. Results are the mean coefficients of each CpG in all validation tests;
c Results represent changes of M-value. Adjusted for child sex, maternal education (college graduate), maternal smoking during pregnancy (never, former, during pregnancy), age at blood draw for DNA methylation, and cell type proportions. Batch effect from plate was adjusted in ComBat. BMIz was included in the ComBat model to protect regression variability;
d Results represent changes of M-value. Adjusted for child sex, maternal education (college graduate), maternal smoking during pregnancy (never, former, during pregnancy), age at the early adolescence visit, age at blood draw for DNA methylation, and cell type proportions. Batch effect from plate was adjusted in ComBat. BMIz was included in the ComBat model to protect regression variability;
e ‘% TE’ denotes the proportion of total effect explained by each mediator, calculated as α*β/TE. In this study, higher BMIz in mid-childhood is associated with higher cardio-metabolic risk score in early adolescence.