Environment- and epigenome-wide association study of obesity in ‘Children of 1997’ birth cohort

  1. Jie Zhao  Is a corresponding author
  2. Bohan Fan
  3. Jian Huang
  4. Benjamin John Cowling
  5. Shiu Lun Ryan Au Yeung
  6. Andrea Baccarelli
  7. Gabriel M Leung
  8. C Mary Schooling
  1. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
  2. Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore
  3. Mailman School of Public Health, Columbia University, United States
  4. City University of New York, School of Public Health and Health policy, United States
4 figures, 8 tables and 4 additional files

Figures

Figure 1 with 1 supplement
Associations of all exposures with body mass index (BMI) and waist–hip ratio (WHR) at age ~11.5 years in the univariable regression in Hong Kong’s ‘Children of 1997’ birth cohort.

(a) Associations of all exposures with body mass index (BMI) at age ~11.5 years in the univariable regression in Hong Kong’s ‘Children of 1997’ birth cohort. (b) Associations of all exposures with waist–hip ratio (WHR) at age ~11.5 years in the univariable regression in Hong Kong’s ‘Children of 1997’ birth cohort. DM, diabetes; edu, education; ASB, artificially sweetened beverages; PA, physical activity; SHS, second-hand smoking; freq, frequency. In total, we included 123 exposures for BMI at 11.5 years and 115 exposures for WHR at 11.5 years. The cut-off lines indicate Bonferroni-corrected p thresholds (p < 0.05/123 = 4.07 × 10−4 for BMI, p < 0.05/115 = 4.35 × 10−4 for WHR).

Figure 1—figure supplement 1
Number of participants in the environment-wide (EWAS) and epigenome-wide association study of adiposity in ’Children of 1997’ birth cohort.
Associations of all exposures with body mass index (BMI) and waist–hip ratio (WHR) at age ~17.6 years in the univariable regression in 3618 participants of Hong Kong’s ‘Children of 1997’ birth cohort in the Biobank Clinical follow-up.

(a) Associations of all exposures with body mass index (BMI) at age ~17.6 years in the univariable regression in 3618 participants of Hong Kong’s ‘Children of 1997’ birth cohort in the Biobank Clinical follow-up. (b) Associations of all exposures with waist–hip ratio (WHR) at age ~17.6 years in the univariable regression in 3618 participants of Hong Kong’s ‘Children of 1997’ birth cohort in the Biobank Clinical follow-up. DM, diabetes; ASB, artificially sweetened beverages; PA, physical activity; SHS, second-hand smoking; freq, frequency. The cut-off lines indicate Bonferroni-corrected p thresholds (p < 0.05/441 exposures = 1.2 × 10−4 for BMI and WHR).

Epigenome-wide association with body mass index (BMI) at age ~23 years in 286 participants from Hong Kong’s ‘Children of 1997’ birth cohort in the follow-up survey.
Figure 3—source data 1

The associations for depicting Figure 3 in the study.

https://cdn.elifesciences.org/articles/82377/elife-82377-fig3-data1-v1.csv
Epigenome-wide association with waist–hip ratio (WHR) at age ~23 years in 286 participants from Hong Kong’s ‘Children of 1997’ birth cohort in the follow-up survey.

Source code file: source code for the environment- and epigenome-wide association study analyses.

Figure 4—source data 1

The associations for depicting Figure 4 in the study.

https://cdn.elifesciences.org/articles/82377/elife-82377-fig4-data1-v1.csv

Tables

Table 1
Baseline characteristics of Hong Kong’s ‘Children of 1997’ birth cohort included in the environment-wide association study (EWAS) of obesity at 11.5, 17.6, and 23 years.
CharacteristicsAt ~11.5 years(n ≤ 7119)At ~17.6 years(n = 3618)At ~23 years(n = 308)
Socio-demographics
SexBoys37321825123
Girls33871793185
Maternal birthplaceNot Hong Kong (migrant)27071509128
Hong Kong41852089179
Highest maternal educationGrade 9 or below28731421124
Grade 10–1130601575127
Grade 12 or above106460057
Household income per head in quintiles at recruitment1st quintile (HK$ 1746 ± 419)126059945
2nd quintile (HK$ 2853 ± 325)128864749
3rd quintile (HK$ 4365 ± 557)126964658
4th quintile (HK$ 6826 ± 883)124365465
5th quintile (HK$ 14,945 ± 15,620)124067467
Maternal age at delivery (mean [SD])30.2 (4.7)30.5 (4.6)30.8 (4.4)
Anthropometrics
Mean height in cm (SD)Boys166.4 (7.5)171.8 (6.0)173.1 (6.3)
Girls158.3 (5.9)159.5 (5.4)160.6 (5.2)
Mean weight in kg (SD)Boys54.6 (11.3)62.7 (11.8)67.3 (15.0)
Girls48.5 (8.0)52.6 (8.9)56.0 (30.5)
Mean BMI (SD)Boys19.2 (3.7)21.1 (3.7)22.4 (4.8)
Girls18.3 (3.1)20.6 (3.3)21.7 (11.5)
Mean WHR (SD)Boys0.84 (0.07)0.79 (0.07)0.87 (0.07)
Girls0.79 (0.06)0.75 (0.05)0.78 (0.07)
Table 2
Associations of selected exposures with body mass index (BMI) and obesity risk at ~11.5 years, and associations of those exposures with BMI at ~17.6 years and with BMI at ~23 years in participants of Hong Kong’s ‘Children of 1997’ birth cohort.
Group namesVariable descriptionWith BMI at ~11.5 years*With obesity risk at ~11.5 years*With BMI at ~17.6 yearsWith BMI at ~23 years
Betap valueOR (95% CI)Betap valueBetap value
Baseline characteristicsSex0.855.65E−222.06 (1.82, 2.32)0.231.99E−030.258.44E−01
Baseline characteristicsBirth weight0.405.40E−151.23 (1.15, 1.32)0.567.84E−060.613.78E−01
Baseline characteristicsSmall for gestational age: birth weight <10% by sex and gestational week distribution in singletons−0.689.93E−060.71 (0.56, 0.89)−0.425.65E−02−0.976.46E−01
SEPNo. of smokers at home0.152.83E−021.15 (1.06, 1.25)0.204.26E−021.073.06E−01
Paternal informationPaternal weight0.051.58E−181.03 (1.02, 1.04)0.041.73E−090.045.68E−01
Maternal informationMaternal weight0.091.84E−491.06 (1.05, 1.07)0.091.30E−280.185.23E−02
Maternal informationPostnatal smoking hygiene (i.e. second-hand smoking by timing [pre- and/or postnatal])0.107.79E−051.06 (1.02, 1.10)0.142.51E−040.363.67E−01
Maternal informationSecond-hand smoke by sources and timing0.082.69E−051.05 (1.02, 1.08)0.103.31E−040.234.54E−01
Maternal informationMother exposed to second-hand smoke during pregnancy0.154.07E−031.08 (1.01, 1.16)0.239.70E−050.325.85E−01
Family historyPaternal diabetes0.695.82E−031.31 (0.93, 1.86)0.312.10E−018.742.08E−04
Family historyMaternal diabetes1.452.47E−052.21 (1.42, 3.44)0.362.23E−01−0.897.67E−01
Family historyGestational diabetes0.682.28E−041.51 (1.18, 1.93)0.571.84E−01−0.839.37E−01
DietWater: frequency of consumption in the last week0.329.45E−061.20 (1.06, 1.36)0.371.89E−041.272.38E−01
LifestyleHaving meals: hours spent yesterday−0.402.06E−030.80 (0.65, 0.99)−0.421.65E−021.713.59E−01
  1. *

    Association of selected exposures with BMI and obesity risk at age ~11.5 years in up to 7119 participants after controlling for confounders.

  2. Association of selected exposures for BMI at age ~11.5 years with BMI at age ~17.6 years (n = 3618) and ~23 years (n = 308) after controlling for confounders.

Table 3
Associations of selected exposures with waist–hip ratio (WHR) at ~11.5 years, and associations of those exposures with WHR at ~17.6 years and with WHR at ~23 years in participants of Hong Kong’s ‘Children of 1997’ birth cohort.
Group namesVariable descriptionWith WHR at ~11.5 years*With WHR at ~17.6 yearsWith WHR at ~23 years
Betap valueBetap valueBetap value
Baseline characteristicsSex0.056.58E−1710.041.28E−880.0824.30E−18
SEPHousing type at birth (home ownership)−0.012.70E−02−0.0018.51E−01−0.014.20E−01
SEPMaternal education level−0.014.90E−05−0.0042.03E−01−0.0019.02E−01
SEPMother’s birthplace−0.011.18E−01−0.012.76E−01−0.0067.97E−01
Maternal informationMaternal weight0.007.98E−100.0011.13E−060.0016.58E−02
Family historyMaternal diabetes0.032.30E−050.011.27E−01−0.0177.82E−01
LifestyleHaving meals: hours spent yesterday−0.018.15E−09−4.73E−031.30E−01−0.0028.11E−01
  1. *

    Association of selected exposures with WHR at age ~11.5 years in up to 7119 participants after controlling for confounders.

  2. Association of selected exposures for WHR at age ~11.5 years with BMI at age ~17.6 years (n = 3618) and ~23 years (n = 308) after controlling for confounders.

Table 4
Associations of selected exposures with body mass index (BMI) and obesity risk at ~17.6 years, and associations of those exposures with BMI at ~23 years in participants from Hong Kong’s ‘Children of 1997’ birth cohort.
Group namesVariable descriptionWith BMI at ~17.6 years*With obesity risk at ~17.6 years*With BMI at ~23 years
Betap valueOR (95% CI)Betap value
Baseline characteristicsSex0.567.84E−061.72 (1.38, 2.14)0.258.44E−01
Baseline characteristicsBirth weight0.231.99E−031.1 (0.97, 1.25)0.613.78E−01
Baseline characteristicsTwin−1.771.05E−030.17 (0.02, 1.27)−3.735.28E−01
Paternal informationPaternal weight0.041.73E−091.03 (1.02, 1.04)0.045.68E−01
Maternal informationMaternal weight0.091.30E−281.05 (1.03, 1.06)0.185.23E−02
Maternal informationMother exposed to second-hand smoke during pregnancy0.239.70E−051.12 (0.99, 1.27)0.029.78E−01
Maternal informationPostnatal smoking hygiene (i.e. second-hand smoking by timing [pre- and/or postnatal])0.096.88E−021.72 (1.38, 2.14)0.781.57E−01
DietChocolate: frequency of consumption in the past week−0.349.02E−060.73 (0.63, 0.84)0.296.92E−01
DietChocolate: no. of servings/time−0.191.09E−040.83 (0.73, 0.95)0.088.69E−01
DietSweets: frequency of consumption in the past week−0.254.18E−040.83 (0.73, 0.95)−0.148.25E−01
DietSweets: no. of servings/time−0.175.42E−050.85 (0.77, 0.94)−0.176.85E−01
DietChinese tea: frequency of consumption in the past week0.271.69E−051.25 (1.13, 1.38)0.296.30E−01
DietChinese tea: no. of cup/time0.172.08E−071.14 (1.08, 1.2)0.185.74E−01
DietChinese herbal tea: frequency of consumption in the past week0.323.16E−041.18 (1.02, 1.36)1.111.82E−01
DietChinese herbal tea: no. of cup/time0.129.17E−041.13 (1.05, 1.22)0.265.01E−01
DietCoffee: frequency of consumption in the past week0.302.90E−051.17 (1.04, 1.32)0.386.05E−01
DietWater: no. of cup/time0.251.07E−091.13 (1.05, 1.22)0.511.97E−01
DietEnergy drinks: no. of cup/time0.141.21E−041.13 (0.99, 1.3)0.664.84E−01
DietWhen consume milk, how often reduced-fat/skim milk0.602.56E−240.7 (0.63, 0.77)1.645.35E−03
DietWhen consume soy milk/flavored drinks, how often lower sugar0.485.14E−110.73 (0.64, 0.82)0.782.55E−01
DietWhen consume soft drinks, how often diet/artificially sweetened drinks0.501.75E−100.7 (0.62, 0.8)0.623.61E−01
DietEating: 1 hr before sleeping−0.762.85E−060.65 (0.47, 0.9)−1.045.04E−01
Children’s HealthParents’ questionnaire: do you consider your child now to be: very thin/underweight; a little bit thin/underweight; about the right weight; a little bit fat/overweight; very fat/overweight; don’t know2.510.00E+007.45 (6.09, 9.12)2.134.12E−04
Children’s HealthSnoring in the past 4 weeks (child)0.769.72E−080.51 (0.4, 0.65)1.303.18E−01
Children’s HealthGrowth problem (child)0.367.41E−081.5 (1.37, 1.64)−0.029.76E−01
Children’s HealthDiabetes (child)0.324.62E−041.29 (1.15, 1.45)0.019.94E−01
Physical activityBall games: no. of times you done past week0.224.04E−031.03 (0.92, 1.17)1.299.89E−02
Physical activityGymnasium: no. of times you done past week0.443.10E−051.14 (0.97, 1.34)0.258.18E−01
Physical activityWhat did you normally do at lunch in the past 7 days0.345.50E−051.22 (1.06, 1.39)−0.228.12E−01
Physical activityHow many nights did you do sports in the past 7 days0.161.13E−020.98 (0.88, 1.08)0.653.43E−01
Physical activityTuesday: how often you did physical activity0.182.15E−031.01 (0.92, 1.11)−0.049.48E−01
Physical activityThursday: how often you did physical activity0.212.86E−041.08 (0.98, 1.2)1.509.65E−03
Moods and feelingsHas he/she gone on eating binges3.225.23E−155.19 (3.18, 8.46)3.373.06E−01
SleepCough or snore loudly0.671.62E−131.43 (1.25, 1.63)1.152.15E−01
SleepHave bad dreams−0.271.87E−030.77 (0.64, 0.91)−0.992.31E−01
Pubertal timingAge of onset of pubic hair−0.562.41E−100.78 (0.67, 0.92)−0.851.24E−03
Pubertal timingAge of menarche (girls)−0.812.46E−270.54 (0.45, 0.64)−1.112.18E−01
  1. *

    Association of selected exposures with BMI and obesity risk at age ~17.6 years in 3618 participants after controlling for confounders.

  2. Association of selected exposures for BMI at age ~17.6 years with BMI at ~23 years (n = 308) after controlling for confounders.

Table 5
Associations of selected exposures with waist–hip ratio (WHR) at ~17.6 years, and associations of those exposures with WHR at ~23 years in participants from Hong Kong’s ‘Children of 1997’ birth cohort.
Group namesVariable descriptionWith WHR at ~17.6 years*With WHR at ~23 years
Betap valueBetap value
Baseline characteristicsSex0.0451.28E−880.0835.71E−18
Maternal informationMaternal weight0.0011.13E−060.0019.38E−02
SEPHousing type at birth (home ownership)−0.0062.70E−02−0.0066.10E−01
DietBiscuits: frequency of consumption in the past week−0.0032.60E−020.0009.36E−01
DietChocolate: frequency of consumption in the past week−0.0041.86E−03−0.0035.20E−01
DietChocolate: no. of servings/time−0.0035.03E−050.0009.11E−01
DietSweets: frequency of consumption in the past week−0.0031.07E−020.0009.80E−01
DietWhen consume soft drinks, how often diet/artificially sweetened drinks0.0051.04E−04–0.0089.36E−02
Children’s HealthParents’ questionnaire: do you consider your child now to be: very thin/underweight; a little bit thin/underweight; about the right weight; a little bit fat/overweight; very fat/overweight; don’t know0.0213.55E−590.0153.02E−04
Children’s HealthWhether experienced musculoskeletal pain in past 4 weeks0.0061.57E−02−0.0018.94E−01
SleepCough or snore loudly0.0072.30E−060.0134.76E−02
SleepSleep disturbance (child)0.0051.93E−030.0036.28E−01
  1. *

    Association of selected exposures with WHR at age ~17.6 years in 3618 participants after controlling for confounders.

  2. Association of selected exposures for WHR at age ~17.6 years with WHR at ~23 years (n = 308) after controlling for confounders.

Table 6
Evidence from published systematic reviews, randomized controlled trials (RCTs) and Mendelian randomization (MR) studies regarding the role of exposures selected in our environment-wide association study (EWAS) in obesity.
ExposurePublished RCTs studiesPublished MR studies
Water consumptionIntervention on promoting water consumption showed no effect on body mass index (BMI; Muckelbauer et al., 2009).NA
Reduced-fat/skim milk consumptionNAMR study on different types of milk consumption (i.e. reduced-fat, skimmed, reduced-sugar milk) among children is lacking. Nevertheless, two MR studies suggested higher dairy intake was associated with higher adult’s BMI (Huang et al., 2018b; Yang et al., 2017).
Coffee consumptionNAGenetically predicted more coffee intake was not associated with obesity, BMI, or waist circumference in two large adult population cohorts (Nordestgaard et al., 2015). Also, most MR studies do not support a role of caffeine consumption on BMI or waist circumstance (Nordestgaard et al., 2015; Cornelis and Munafo, 2018).
Chocolate consumptionMeta-analysis of RCTs did not support a significant effect of cocoa/dark chocolate supplementation on body weight or BMI (Kord-Varkaneh et al., 2019).NA
DiabetesNAMR study supported genetic predisposition to higher childhood BMI was associated with risk of type 2 diabetes (Geng et al., 2018).
Binge eatingNAThe MR study suggests a bi-directional association, that is, more binge eating and overeating are associated with higher BMI in later life, and higher children’s BMI is associated with more binge eating (Reed et al., 2017).
Physical exercisesA systematic review shows school based RCTs targeting physical activity, or physical activity combined with diet interventions, were effective in reducing BMI among children (Bleich et al., 2018).Genetically predicted more physical activity was associated with lower BMI (Carrasquilla et al., 2022).
SnoringNAMR study suggests genetically predicted BMI is related to snoring (Campos et al., 2020).
Pubertal timingNAGenetically predicted earlier age at puberty was related to higher BMI (Gill et al., 2018), but pleiotropy might exist (Gill et al., 2018). The association attenuated towards the null after controlling for prior BMI (Bell et al., 2018). It is also possible that genetically predicted BMI was associated with earlier age at puberty (Chen et al., 2019).
Birth weightNAMR analyses indicated positive causal associations of birthweight with BMI in the UKB (Zanetti et al., 2018).
Maternal adiposity during pregnancyNAUsing BMI polygenic risk scores calculated from maternal non-transmitted alleles, previous MR studies using mother–offspring pairs from two large UK cohorts did not support causal associations between maternal pre/early pregnancy BMI and offspring adolescent adiposity (Bond et al., 2022; Richmond et al., 2017).
Table 7
Associations of CpGs with body mass index (BMI) at age ~23 years in 286 participants from Hong Kong’s ‘Children of 1997’ birth cohort in the follow-up survey.
CpGGeneBetap value
cg00379266RBM16−69.79.8E−07
cg01525498RPTOR−40.24.6E−10
cg02200725-−18.94.2E−07
cg04563671SCN2B14.81.6E−07
cg07243141-24.69.0E−07
cg08205320-−21.92.6E−08
cg09639369SLC24A4−15.75.7E−07
cg11937362-1099.5E−07
cg12484266C2835.7E−09
cg14630200RPS6KA2−45.17.1E−12
cg14850190KSR1103.24.3E−07
cg18681028-−48.57.6E−16
cg18893311-30.87.5E−08
cg22197830TXNDC15−68.84.9E−07
cg25356423ZNF827−141.6E−07
cg25903177-−31.45.8E−07
cg26347007GTF3C3−45.88.0E−07
  1. CpGs reaching significance of p < 1 × 10−6 were shown in the table.

Table 8
Associations of CpGs with waist–hip ratio (WHR) at age ~23 years in 286 participants from Hong Kong’s ‘Children of 1997’ birth cohort in the follow-up survey.
CpGGeneBetap value
cg00952960LANCL2−0.543.0E−11
cg04405211C6orf1950.359.7E−07
cg05059349-0.263.7E−07
cg07416310DCDC2−0.458.8E−08
cg09422806NFIC0.53.4E−08
cg09684856DIRC3−0.791.4E−07
cg09907395RNF2131.092.2E−07
cg11344771LPP−0.791.0E−08
cg14630200RPS6KA2−0.465.4E−07
cg17007012MIR4535−0.356.6E−11
cg17043713ZNF1410.558.1E−08
cg17769811CTRL−0.761.3E−09
cg19481727MIR7641-2−0.365.4E−07
cg19579176-−0.359.9E−07
cg22364817-−1.466.7E−07
cg25097095LYRM9−0.418.8E−09
cg27384074OPA30.551.7E−07
  1. CpGs reaching significance of p < 1 × 10−6 were shown in the table.

Additional files

MDAR checklist
https://cdn.elifesciences.org/articles/82377/elife-82377-mdarchecklist1-v1.docx
Supplementary file 1

Categorization and data sources for exposures.

https://cdn.elifesciences.org/articles/82377/elife-82377-supp1-v1.xls
Supplementary file 2

Associations of selected exposures with BMI after adjusting for time difference in participants of Hong Kong’s “Children of 1997” birth cohort.

https://cdn.elifesciences.org/articles/82377/elife-82377-supp2-v1.docx
Source code 1

Main analysis code.

https://cdn.elifesciences.org/articles/82377/elife-82377-code1-v1.zip

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  1. Jie Zhao
  2. Bohan Fan
  3. Jian Huang
  4. Benjamin John Cowling
  5. Shiu Lun Ryan Au Yeung
  6. Andrea Baccarelli
  7. Gabriel M Leung
  8. C Mary Schooling
(2023)
Environment- and epigenome-wide association study of obesity in ‘Children of 1997’ birth cohort
eLife 12:e82377.
https://doi.org/10.7554/eLife.82377