Appendix S1.

Factor analysis procedure for reducing IGF2 methylation data and results

Procedure:

Factor analysis proceeded in two main steps. First, exploratory factor

analysis (EFA) was used to establish the covariance structure among the

139 IGF2 probes at birth in order to extract a smaller set of underlying

factors, deleting CpGs with low correlations as needed. The optimal

number of factors was determined by evaluating the Scree-plot and

comparing fit statistics between models estimating 1 to 5 factors. Model

fit was first established using the chi-square statistic. In instances where

there were significant chi-square values, we further examined relative fit

indices, including the mean square error of approximation (RMSEA;

acceptable fit ≤ 0.08), as well as the comparative fit index and the

Tucker-Lewis index (CFI and TLI; acceptable fit ≥ 0.90). In the second

step, confirmatory factor analysis (CFA) was run to validate the factor

structure identified by the EFA.

Results:

Using EFA, we identified 3 IGF2 methylation factors at birth

(containing 37, 11, and 5 probes, respectively), which showed

acceptable model fit: X2 (1428) = 2185.61, p < .001; RMSEA = 0,04;

TLI = .87; CFI = .86. We then used CFA to validate the 3-factor model.

See SI2 for probe descriptive statistics, standardized loadings and model

fit indices. Correlations between the IGF2 probes at birth can be found

in SI3. For each IGF2 factor, we calculated the average DNA

methylation level by taking the mean of the relevant CpG sites.

Table S1. Confirmatory Factor Model of IGF2 methylation patterns at birth
Standardized
estimate Mean SD
Factor 1
CG01368777 0.726 0.18 0.03
CG01667319 0.665 0.11 0.02
CG02166532 0.724 0.15 0.03
CG02835822 0.512 0.14 0.03
CG03760951 0.543 0.12 0.03
CG05075097 0.424 0.09 0.02
CG05203776 0.615 0.17 0.03
CG05452899 0.437 0.13 0.02
CG05859777 0.413 0.10 0.03
CG07583420 0.626 0.08 0.02
CG08686462 0.386 0.54 0.04
CG08986368 0.505 0.10 0.02
CG09694722 0.743 0.12 0.02
CG10337079 0.409 0.14 0.02
CG10501065 0.528 0.21 0.04
CG10659464 0.525 0.21 0.04
CG11701022 0.675 0.19 0.03
CG12322132 0.679 0.13 0.02
CG12877935 0.472 0.15 0.02
CG13756879 0.420 0.09 0.02
CG13791131 0.421 0.13 0.03
CG15393937 0.351 0.12 0.03
CG15508379 0.342 0.15 0.02
CG17462140 0.676 0.13 0.03
CG19371526 0.681 0.15 0.03
CG20339650 0.814 0.17 0.03
CG20728696 0.448 0.12 0.02
CG21237591 0.379 0.20 0.04
CG22225943 0.392 0.20 0.04
CG22287492 0.545 0.19 0.04
CG23905216 0.554 0.20 0.04
CG24047810 0.549 0.16 0.03
CG24366657 0.448 0.08 0.02
CG24917382 0.596 0.16 0.03
CG25163476 0.883 0.15 0.03
CG25574024 0.424 0.10 0.03
CG25742037 0.361 0.50 0.06
Model fit: χ2(629) = 957.17, p < 0.001; RMSEA=0.04; CFI = 0.91; TLI = 0.90

Factor 2
CG00613255 0.480 0.77 0.03
CG06029905 0.528 0.78 0.03
CG09503234 0.345 0.93 0.02
CG09864961 0.499 0.70 0.03
CG10732560 0.362 0.91 0.02
CG12219390 0.393 0.86 0.04
CG16711450 0.643 0.74 0.03
CG19297427 0.438 0.69 0.04
CG23390871 0.741 0.73 0.03
CG24522478 0.541 0.75 0.03
CG25601886 0.610 0.72 0.03
Model fit: χ2(44) = 54.55, p = 0.13

Factor 3
CG10991175 0.646 0.68 0.04
CG13993218 0.352 0.72 0.06
CG21574853 0.781 0.74 0.04
CG24338752 0.668 0.72 0.05
CG25336198 0.742 0.58 0.05
Model fit: χ2(5) = 3.32, p = 0.65
Appendix S2. Location of IGF2 methylation probes included in the study, and how these are grouped into factors (that is, Factor 1: red; Factor 2: green; Factor 3: grey)
or 2: green; Factor 3: grey)
cg12219390 cg16711450 cg19297427 cg23390871 cg24522478 cg25601886 cg10991175 cg13993218 cg21574853 cg24338752 cg25336198
-,166** -,293**
-.100 -,346** -,318** -,319** -,112*
-.013 -.095 -.024 .005
.003 .000 .073 .000 .000 .000 .045 .817 .089 .671 .932
321 321 321 321 321 321 321 321 321 321 321
-,160** -,191** -.062 -,255** -,232** -,198** -.051 -.009 -.043 -.030 -.063
.004 .001 .267 .000 .000 .000 .366 .869 .448 .587 .264
321 321 321 321 321 321 321 321 321 321 321
-,178** -,307** -.088 -,432** -,396** -,422** -.050 .068 -.082 -.004 -.025
.001 .000 .116 .000 .000 .000 .373 .223 .144 .941 .652
321 321 321 321 321 321 321 321 321 321 321
-,162** -,163** .004 -,137* -,200** -,177** .053 -.010 -.021 .074 .032
.004 .003 .937 .014 .000 .001 .348 .856 .712 .189 .569
321 321 321 321 321 321 321 321 321 321 321
-.108 -,190**
-.031 -,208**
-,223**
-,206**
-.025 -.016 .032 -.004 -.020
.054 .001 .579 .000 .000 .000 .650 .775 .570 .938 .717
321 321 321 321 321 321 321 321 321 321 321
-,114 *
-,187**
-.070 -,307**
-,226**
-,247**
.017 -.035 -.082 -.083 -,138*
.041 .001 .213 .000 .000 .000 .761 .526 .143 .140 .013
321 321 321 321 321 321 321 321 321 321 321
-.098 -,239**
-.012 -,295**
-,320**
-,211**
-.008 .057 -.086 -.024 -.077
.080 .000 .836 .000 .000 .000 .885 .312 .123 .664 .170
321 321 321 321 321 321 321 321 321 321 321
-.102 -,223**
-,200**
-,249**
-,168**
-,196**
-.070 .000 -.001 -.024 -.035
.069 .000 .000 .000 .003 .000 .208 .998 .989 .672 .527
321 321 321 321 321 321 321 321 321 321 321
-.069 -,177**
-.037 -,196**
-,213**
-,157**
.053 .010 .016 .071 .073
.215 .001 .506 .000 .000 .005 .340 .856 .776 .205 .194
321 321 321 321 321 321 321 321 321 321 321
-,158** -,258** -.015 -,310** -,295** -,314** -,130* .053 -.105 .013 -.066
 .005 .000 .782 .000 .000 .000 .020 .344 .059 .816 .241
321 321 321 321 321 321 321 321 321 321 321
.051 -,140 *
.023 -,110 *
-,146**
-,145**
.059 .008 -.020 -.055 .086
.367 .012 .686 .048 .009 .010 .295 .883 .720 .330 .125
321 321 321 321 321 321 321 321 321 321 321
-.047 -,154**
-.106 -,280**
-,252**
-,154**
-.084 -.009 -.024 -.013 -.028
.403 .006 .058 .000 .000 .006 .132 .867 .665 .810 .618
321 321 321 321 321 321 321 321 321 321 321
-,128 *
-,352**
-.086 -,312**
-,327**
-,309**
-,140 *
.004 -,133 *
-.106 -.066
.021 .000 .126 .000 .000 .000 .012 .940 .017 .058 .237
321 321 321 321 321 321 321 321 321 321 321
-,116* -,244** -.104 -,245** -,239** -,289** -,190** -.037 -,194** -.079 -,147**
.038 .000 .062 .000 .000 .000 .001 .511 .000 .160 .009
321 321 321 321 321 321 321 321 321 321 321
-,182** -,343** -,183** -,372** -,294** -,304** -.014 -.002 -.029 .021 .001
.001 .000 .001 .000 .000 .000 .803 .967 .607 .702 .981
321 321 321 321 321 321 321 321 321 321 321
-,112 *
-,205**
-.077 -,229**
-,223**
-,186**
-.073 -.020 -.093 -.058 -.002
.046 .000 .171 .000 .000 .001 .194 .716 .097 .300 .968
321 321 321 321 321 321 321 321 321 321 321
-,154**
-,295**
-.080 -,354**
-,377**
-,298**
.020 .009 .035 .106 .049
.006 .000 .154 .000 .000 .000 .724 .870 .527 .057 .381
321 321 321 321 321 321 321 321 321 321 321
-,159**
-,295**
-.103 -,368**
-,247**
-,284**
-.060 -.010 -.094 -.036 -.090
.004 .000 .065 .000 .000 .000 .287 .859 .094 .526 .109
321 321 321 321 321 321 321 321 321 321 321
-,146**
-,249**
-,171**
-,313**
-,267**
-,275**
-.053 .017 -.029 .043 -.028
.009 .000 .002 .000 .000 .000 .344 .767 .602 .442 .622
321 321 321 321 321 321 321 321 321 321 321
-.085 -,128 *
-.087 -,286**
-,236**
-,185**
-.108 .013 -.074 -.067 -.004
.127 .022 .118 .000 .000 .001 .053 .811 .185 .228 .938
321 321 321 321 321 321 321 321 321 321 321
-,123* -.058 .015 -,151** -,215** -,159** -,136* .073 -,110* -.039 -.090
 .028 .296 .791 .007 .000 .004 .015 .194 .048 .489 .106
321 321 321 321 321 321 321 321 321 321 321
-.081 -,120 *
-.032 -.085 -.084 -.078 -.095 -.105 -.101 -,165
**
-.098
.147 .031 .573 .128 .135 .164 .090 .061 .069 .003 .078
321 321 321 321 321 321 321 321 321 321 321
-.078 -,129 *
-.013 -,134 *
-,169**
-,184**
-.028 -.066 -.033 -.060 -.082
.163 .021 .815 .016 .002 .001 .613 .241 .554 .287 .142
321 321 321 321 321 321 321 321 321 321 321
-,202**
-,323**
-.084 -,316**
-,273**
-,306**
-.102 -.030 -.023 .036 .017
.000 .000 .133 .000 .000 .000 .069 .593 .677 .524 .765
321 321 321 321 321 321 321 321 321 321 321
-.095 -,301** -.098 -,385** -,345** -,324** -,176** -.001 -,176** -.047 -.096
.090 .000 .079 .000 .000 .000 .002 .989 .002 .401 .087
321 321 321 321 321 321 321 321 321 321 321
-,191** -,341** -,158** -,420** -,428** -,411** -,132* .005 -.058 -.030 -.039
.001 .000 .005 .000 .000 .000 .018 .930 .297 .590 .491
321 321 321 321 321 321 321 321 321 321 321
-,166**
-,126 *
.005 -,253**
-,220**
-,193**
-.092 .011 -.097 -.051 -.052
.003 .024 .933 .000 .000 .001 .100 .841 .083 .361 .356
321 321 321 321 321 321 321 321 321 321 321
-.014 -,153**
-.103 -,247**
-,259**
-,122 *
-.053 .007 .063 .075 -.025
.804 .006 .066 .000 .000 .029 .346 .898 .259 .179 .657
321 321 321 321 321 321 321 321 321 321 321
-.052 -,128 *
-,133 *
-,184**
-,238**
-,145**
-.030 .004 .039 ,121 *
-.073
.357 .022 .017 .001 .000 .009 .595 .947 .483 .030 .191
321 321 321 321 321 321 321 321 321 321 321
-.067 -,189**
-.073 -,237**
-,247**
-,185**
-,150**
-.029 -.058 -.094 -.109
.232 .001 .194 .000 .000 .001 .007 .611 .302 .094 .052
321 321 321 321 321 321 321 321 321 321 321
-.087 -,185**
-,128 *
-,247**
-,243**
-,152**
-.081 -.054 -,120 *
-.030 -.072
.119 .001 .021 .000 .000 .006 .148 .332 .032 .590 .200
321 321 321 321 321 321 321 321 321 321 321
-,233** -,250** .013 -,265** -,219** -,263** -,120* -.049 -.107 -.050 -.053
 .000 .000 .820 .000 .000 .000 .032 .384 .056 .372 .340
321 321 321 321 321 321 321 321 321 321 321
-,179
**
-,145
**
-,130 *
-,201**
-,241**
-,159**
.016 -.013 .045 .098 .038
.001 .009 .019 .000 .000 .004 .769 .822 .425 .078 .493
321 321 321 321 321 321 321 321 321 321 321
-,174
**
-,219
**
-,119 *
-,333**
-,319**
-,284**
.019 .005 -.013 .056 -.037
.002 .000 .034 .000 .000 .000 .740 .933 .811 .319 .504
321 321 321 321 321 321 321 321 321 321 321
-,244
**
-,350
**
-.092 -,434**
-,392**
-,358**
-,117 *
-.006 -.086 -.005 -.056
.000 .000 .100 .000 .000 .000 .035 .908 .124 .926 .318
321 321 321 321 321 321 321 321 321 321 321
-,133* -,124* -.037 -,194** -,232** -,183** -.067 .026 -.071 -.021 -.039
.017 .026 .506 .000 .000 .001 .228 .647 .207 .711 .487
321 321 321 321 321 321 321 321 321 321 321
-,118* -.066 -.016 -,120* -,253** -,233** -.109 -.043 -,119* -.107 -.076
.034 .237 .772 .031 .000 .000 .051 .446 .033 .056 .176
321 321 321 321 321 321 321 321 321 321 321
,147**
,278**
,188**
,314 **
,274 **
,336 **
,268**
,197**
,379**
.089 ,271**
.008 .000 .001 .000 .000 .000 .000 .000 .000 .111 .000
321 321 321 321 321 321 321 321 321 321 321
,178**
,405**
,308**
,375 **
,280 **
,267 **
,120 *
,119 *
.085 -.105 .050
.001 .000 .000 .000 .000 .000 .032 .033 .130 .059 .375
321 321 321 321 321 321 321 321 321 321 321
,210**
,244**
,141 *
,231 **
,140 *
,232 **
,131 *
,140 *
,111 *
.050 .091
.000 .000 .011 .000 .012 .000 .019 .012 .047 .367 .102
321 321 321 321 321 321 321 321 321 321 321
,184**
,304**
,181**
,353 **
,328 **
,372 **
,284**
.070 ,196**
,113*
,226**
.001 .000 .001 .000 .000 .000 .000 .212 .000 .043 .000
321 321 321 321 321 321 321 321 321 321 321
,189**
,213**
,159**
,301 **
,155 **
,227 **
.077 .047 .014 -.101 .030
.001 .000 .004 .000 .005 .000 .170 .402 .802 .072 .593
321 321 321 321 321 321 321 321 321 321 321
1 ,264** ,194** ,302** ,218** ,252** .027 .081 .002 -.002 .061
 .000 .000 .000 .000 .000 .633 .147 .973 .973 .277
321 321 321 321 321 321 321 321 321 321 321
,264**
1 ,323**
,534**
,234**
,382**
,132 *
,175**
.074 -,111 *
.024
.000 .000 .000 .000 .000 .018 .002 .185 .047 .674
321 321 321 321 321 321 321 321 321 321 321
,194**
,323**
1 ,310**
,215**
,255**
,147**
.062 -.010 -.042 .066
.000 .000 .000 .000 .000 .008 .271 .856 .451 .237
321 321 321 321 321 321 321 321 321 321 321
,302**
,534**
,310**
1 ,447**
,416**
,170**
.101 .032 -,110 *
.035
.000 .000 .000 .000 .000 .002 .070 .566 .049 .531
321 321 321 321 321 321 321 321 321 321 321
,218** ,234** ,215** ,447** 1 ,385** ,180** -.002 ,116* .032 ,178**
.000 .000 .000 .000 .000 .001 .972 .038 .565 .001
321 321 321 321 321 321 321 321 321 321 321
,252** ,382** ,255** ,416** ,385** 1 ,209** .100 ,272** ,137* ,139*
.000 .000 .000 .000 .000 .000 .072 .000 .014 .013
321 321 321 321 321 321 321 321 321 321 321
.027 ,132 *
,147**
,170**
,180**
,209**
1 ,292**
,506**
,426 **
,463**
.633 .018 .008 .002 .001 .000 .000 .000 .000 .000
321 321 321 321 321 321 321 321 321 321 321
.081 ,175**
.062 .101 -.002 .100 ,292**
1 ,270**
,213 **
,253**
.147 .002 .271 .070 .972 .072 .000 .000 .000 .000
321 321 321 321 321 321 321 321 321 321 321
.002 .074 -.010 .032 ,116 *
,272**
,506**
,270**
1 ,518 **
,591**
.973 .185 .856 .566 .038 .000 .000 .000 .000 .000
321 321 321 321 321 321 321 321 321 321 321
-.002 -,111 *
-.042 -,110 *
.032 ,137 *
,426**
,213**
,518**
1 ,511**
.973 .047 .451 .049 .565 .014 .000 .000 .000 .000
321 321 321 321 321 321 321 321 321 321 321
.061 .024 .066 .035 ,178**
,139 *
,463**
,253**
,591**
,511 **
1
.277 .674 .237 .531 .001 .013 .000 .000 .000 .000
321 321 321 321 321 321 321 321 321 321 321
Multiple group path analysis. Solid arrowed lines indicate standardized path coefficients that survived bootstrap-c

(i.e. significant paths) for EOP versus low CP youth or averaged across all youth.

ADHD=attention deficit hyperactivity disorder; EOP=early-onset persistent; CP=conduct problems

 Figure S1: Unadjusted model not controlling for prenatal and postnatal cumulative risk factors

cients that survived bootstrap-corrected confidence intervals

onduct problems

Figure S1: Unadjusted model

stnatal cumulative risk factors