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Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach

BACKGROUND: DNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the...

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Autores principales: Neumann, Alexander, Pingault, Jean-Baptiste, Felix, Janine F., Jaddoe, Vincent W. V., Tiemeier, Henning, Cecil, Charlotte, Walton, Esther
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9020033/
https://www.ncbi.nlm.nih.gov/pubmed/35440009
http://dx.doi.org/10.1186/s13148-022-01268-w
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author Neumann, Alexander
Pingault, Jean-Baptiste
Felix, Janine F.
Jaddoe, Vincent W. V.
Tiemeier, Henning
Cecil, Charlotte
Walton, Esther
author_facet Neumann, Alexander
Pingault, Jean-Baptiste
Felix, Janine F.
Jaddoe, Vincent W. V.
Tiemeier, Henning
Cecil, Charlotte
Walton, Esther
author_sort Neumann, Alexander
collection PubMed
description BACKGROUND: DNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R(2)(Methylation)) towards childhood phenotypes is unknown. An estimate of R(2)(Methylation) would provide context regarding the importance of DNA methylation explaining variance in health outcomes. We therefore estimated the variance explained by epigenome-wide cord blood methylation (R(2)(Methylation)) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n = 775) and Generation R (n = 1382). RESULTS: Using information from > 470,000 autosomal probes we estimated that DNA methylation at birth explains 32% (SD(CV) = 0.06) of gestational age variance and 5% (SD(CV) = 0.02) of birth weight variance. The R(2)(Methylation) estimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations. CONCLUSIONS: The results suggest that cord blood methylation explains a moderate degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the true R(2)(Methylation) for these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth.
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spelling pubmed-90200332022-04-21 Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach Neumann, Alexander Pingault, Jean-Baptiste Felix, Janine F. Jaddoe, Vincent W. V. Tiemeier, Henning Cecil, Charlotte Walton, Esther Clin Epigenetics Research BACKGROUND: DNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R(2)(Methylation)) towards childhood phenotypes is unknown. An estimate of R(2)(Methylation) would provide context regarding the importance of DNA methylation explaining variance in health outcomes. We therefore estimated the variance explained by epigenome-wide cord blood methylation (R(2)(Methylation)) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n = 775) and Generation R (n = 1382). RESULTS: Using information from > 470,000 autosomal probes we estimated that DNA methylation at birth explains 32% (SD(CV) = 0.06) of gestational age variance and 5% (SD(CV) = 0.02) of birth weight variance. The R(2)(Methylation) estimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations. CONCLUSIONS: The results suggest that cord blood methylation explains a moderate degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the true R(2)(Methylation) for these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth. BioMed Central 2022-04-19 /pmc/articles/PMC9020033/ /pubmed/35440009 http://dx.doi.org/10.1186/s13148-022-01268-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Neumann, Alexander
Pingault, Jean-Baptiste
Felix, Janine F.
Jaddoe, Vincent W. V.
Tiemeier, Henning
Cecil, Charlotte
Walton, Esther
Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach
title Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach
title_full Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach
title_fullStr Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach
title_full_unstemmed Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach
title_short Epigenome-wide contributions to individual differences in childhood phenotypes: a GREML approach
title_sort epigenome-wide contributions to individual differences in childhood phenotypes: a greml approach
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9020033/
https://www.ncbi.nlm.nih.gov/pubmed/35440009
http://dx.doi.org/10.1186/s13148-022-01268-w
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