Environment- and epigenome-wide association study of obesity in ‘Children of 1997’ birth cohort
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eLife assessment
This study presents useful information on the environmental and epigenomic associations of obesity in children and adolescents. The data were collected and analyzed using a solid and validated methodology and can be referenced at the clinics and health authorities to make a guideline and a policy strategy.
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Abstract
Increasing childhood obesity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of obesity at the onset and end of puberty in Hong Kong, the most economically developed major Chinese city.
Methods:
We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of obesity to systematically assess associations with body mass index (BMI) and waist–hip ratio (WHR) in Hong Kong’s population-representative ‘Children of 1997’ birth cohort. Univariable linear regression was used to select exposures related to obesity at ~11.5 years (BMI and obesity risk n ≤ 7119, WHR n = 5691) and ~17.6 years ( n = 3618) at Bonferroni-corrected significance, and multivariable regression to adjust for potential confounders followed by replicated multivariable regression ( n = 308) and CpG by CpG analysis ( n = 286) at ~23 years. Findings were compared with evidence from published randomized controlled trials (RCTs) and Mendelian randomization (MR) studies.
Results:
At ~11.5 and~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as 7 and 12 associated with WHR, respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with obesity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, and binge eating are consistent with available evidence from RCTs or MR studies. We found 17 CpGs related to BMI and 17 to WHR.
Conclusions:
These novel insights into potentially modifiable factors associated with obesity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings.
Funding:
This study including the follow-up survey and epigenetics testing was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction of the samples used for epigenetic testing was supported by CFS-HKU1.
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Author Response
Reviewer #1 (Public Review):
The authors assessed the association between exposures and obesity by environment-wide and epigenome-wide association studies. The strength of this study is that exposures, body mass index, and waist-hip ratio were measured three times from adolescence to early adulthood, and the associations were repeatedly evaluated. A weakness of this study is that a loose significance threshold was used for the epigenome-wide association study and only a small number of study subjects were measured in early adulthood. Since this is an observational study, the confounding effect should be considered when interpreting the exposures associated with obesity reported in this study.
Thank you very much for your positive comments and helpful suggestions. We agree that the study has the limitation of the …
Author Response
Reviewer #1 (Public Review):
The authors assessed the association between exposures and obesity by environment-wide and epigenome-wide association studies. The strength of this study is that exposures, body mass index, and waist-hip ratio were measured three times from adolescence to early adulthood, and the associations were repeatedly evaluated. A weakness of this study is that a loose significance threshold was used for the epigenome-wide association study and only a small number of study subjects were measured in early adulthood. Since this is an observational study, the confounding effect should be considered when interpreting the exposures associated with obesity reported in this study.
Thank you very much for your positive comments and helpful suggestions. We agree that the study has the limitation of the loose significance threshold used for the epigenome-wide association study and the limited sample size in early adulthood. Following the reviewer’s suggestion, we have revised the threshold of significance in the epigenome-wide association study to 1×10-6. We have added more discussion on confounding, and we are more cautious in the interpretation of the results.
Reviewer #2 (Public Review):
Since this study is a long-term cohort study in children and adolescents, it is advisable to decide whether to highlight differences by age group or to show consistent effect after exposure. In particular, obesity and related diseases are closely related to socio-economic environmental factors, and its impact might be different according to age (group) at exposure.
Thank you very much for your insightful suggestions. We agree that the associations of exposures, including socio-economic and environmental factors, with obesity might vary by age, that is why we examined the associations of early life exposures with BMI and WHR at different ages. It is possible that the same exposure may impact obesity differently by age, so we also assessed the associations of exposures selected at earlier ages of BMI/WHR with BMI/WHR at older ages, and compared consistency in the direction of association at different time points. We have added more explanation in the introduction and methods:
(Introduction, paragraph 4)
“Considering that exposures related to obesity at the outset and at the end of puberty may be different, and the associations of the same exposure with obesity may vary by age, we conducted the EWAS at different ages.”
(Methods, Statistical analysis)
“Third, to assess whether the associations differed by age, we checked the associations for the selected exposures from the earlier age groups (~11.5 years and ~17.6 years) in the follow-up survey (n=308) at age ~23 years and compared the direction of associations with those at earlier age groups (~11.5 years and ~17.6 years). Associations with consistent directions of associations in earlier age groups (~11.5 years or ~17.6 years) with those at ~23 years suggest a consistent association by age.”
The part described in comparison with previous studies is a good attempt. However, some results are consistent with those of previous studies and some are not. This may be related to the time difference in socio-economic environmental factors rather than simply the difference between the West and China (Hong Kong). According to modernization/urbanization, changes in living environment, changes in family relationships, and changes in the care environment can also be factors especially in children.
Thank you very much for your positive comments and raising this interesting point. We totally agree that inconsistency with results of previous studies is not merely due to the difference between the West and China (Hong Kong), but also related to changes in structural socio-economic and environmental factors, as well as changes in living environment, family relationships, social and community network, housing and care environment, that affect individuals’ health. Hence, we provided the necessary clarification by adding the following sentences:
(Discussion, Strengths and Limitations)
“Fourth, the inconsistency between some of our findings and previous studies, such as chocolate, sweets, tea and coffee consumption, should be interpreted cautiously. It may not only reflect differences between the West and China (Hong Kong), but also may be due to changes in structural socio-economic and environmental factors, as well as changes in living environment, family relationships, social and community networks, housing and the care environment.”
In studying the effect of environment on gene expression, it can be thought that the influence of genes and the degree of expression might be different depending on the age of the subject (newborn, infant, infant, adolescent, adult) duration of exposure and these still need to be elucidated.
Thank you very much for raising this important point. We fully agree with you. It would be interesting to examine the association of gene expression at different ages with obesity. However, we only collected blood samples at the Biobank Clinical follow-up (age ~17.6 years), so in this study we only conducted the epigenome-wide association study for DNA methylation at ~17.6 years with BMI and WHR at ~23 years. We have added this in the limitation:
(Discussion, Strengths and limitations)
“Fifth, we only collected blood samples at the Biobank Clinical follow-up (age ~17.6 years), so we only conducted the epigenome-wide association study for DNA methylation at ~17.6 years. It would be worthwhile to examine the association of DNA methylation at different ages with obesity.”
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eLife assessment
This study presents useful information on the environmental and epigenomic associations of obesity in children and adolescents. The data were collected and analyzed using a solid and validated methodology and can be referenced at the clinics and health authorities to make a guideline and a policy strategy.
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Reviewer #1 (Public Review):
The authors assessed the association between exposures and obesity by environment-wide and epigenome-wide association studies. The strength of this study is that exposures, body mass index, and waist-hip ratio were measured three times from adolescence to early adulthood, and the associations were repeatedly evaluated. A weakness of this study is that a loose significance threshold was used for the epigenome-wide association study and only a small number of study subjects were measured in early adulthood. Since this is an observational study, the confounding effect should be considered when interpreting the exposures associated with obesity reported in this study.
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Reviewer #2 (Public Review):
Since this study is a long-term cohort study in children and adolescents, it is advisable to decide whether to highlight differences by age group or to show consistent effect after exposure. In particular, obesity and related diseases are closely related to socio-economic environmental factors, and its impact might be different according to age (group) at exposure.
The part described in comparison with previous studies is a good attempt. However, some results are consistent with those of previous studies and some are not. This may be related to the time difference in socio-economic environmental factors rather than simply the difference between the West and China (Hong Kong). According to modernization/urbanization, changes in living environment, changes in family relationships, and changes in the care …
Reviewer #2 (Public Review):
Since this study is a long-term cohort study in children and adolescents, it is advisable to decide whether to highlight differences by age group or to show consistent effect after exposure. In particular, obesity and related diseases are closely related to socio-economic environmental factors, and its impact might be different according to age (group) at exposure.
The part described in comparison with previous studies is a good attempt. However, some results are consistent with those of previous studies and some are not. This may be related to the time difference in socio-economic environmental factors rather than simply the difference between the West and China (Hong Kong). According to modernization/urbanization, changes in living environment, changes in family relationships, and changes in the care environment can also be factors especially in children.
In studying the effect of environment on gene expression, it can be thought that the influence of genes and the degree of expression might be different depending on the age of the subject (newborn, infant, infant, adolescent, adult) duration of exposure and these still need to be elucidated.
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