DNA methylation signatures of breastfeeding in buccal cells collected in mid-childhood

Veronika V. Odintsova; Fiona A. Hagenbeek; Matthew Suderman; Doretta Caramaschi; Catharina E.M. van Beijsterveldt; Noah A. Kallsen; Erik A. Ehli; Gareth E. Davies; Gennady T. Sukhikh; Vassilios Fanos; Caroline Relton; Meike Bartels; Dorret I. Boomsma; Jenny van Dongen

doi:10.3390/nu11112804

DNA methylation signatures of breastfeeding in buccal cells collected in mid-childhood

Veronika V. Odintsova^*, Fiona A. Hagenbeek, Matthew Suderman, Doretta Caramaschi, Catharina E.M. van Beijsterveldt, Noah A. Kallsen, Erik A. Ehli, Gareth E. Davies, Gennady T. Sukhikh, Vassilios Fanos, Caroline Relton, Meike Bartels, Dorret I. Boomsma, Jenny van Dongen

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized ('never' vs. 'ever'). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10-8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

Original language	English
Article number	2804
Pages (from-to)	1-26
Number of pages	26
Journal	Nutrients
Volume	11
Issue number	11
DOIs	https://doi.org/10.3390/nu11112804
Publication status	Published - 17 Nov 2019

Funding

Funding: V.V.O. is supported by Amsterdam Public Health research institute, and the Russian Foundation for Basic Research (20-015-00496). The Netherlands Twin Register acknowledges funding from multiple grants from the Netherlands Organization for Scientific research (NWO), including NWO-Grant 480-15-001/674: Netherlands Twin Registry Repository; the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI—NL, 184.021.007 and 184.033.111); OCW_Gravity program—NWO-024.001.003 Consortium for Individual Development) and the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA). The methylation work, J.v.D. and F.H. were supported by funding from the European Union Seventh Framework Program (FP7/2007–2013) under grant agreement no 602768 (ACTION). J.v.D. is supported by the NWO-funded X-omics project (184.034.019) and D.I.B. the KNAW Academy Professor Award (PAH/6635). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by the BBSRC (grant numbers BBI025751/1 and BB/I025263/1). C.R. and D.C. are funded by the MRC (grant numbers MC_UU_00011/5 and MC_UU_00011/1). This publication is the work of the authors and V.V.O. and J.v.D. will serve as guarantors for the contents of this paper.

Funders	Funder number
Amsterdam Public Health Research Institute
Consortium for Individual Development
European Union Seventh Framework Program
FP7/2007	ACTION
NTR
NWO-024
NWO-Grant	184.033.111
NWO-funded	184.034.019, PAH/6635
Netherlands Organization for Scientific Research
UK Medical Research Council and Wellcome	102215/2/13/2
Center for Outcomes Research and Evaluation, Yale School of Medicine
Seventh Framework Programme	602768
Biotechnology and Biological Sciences Research Council	BBI025751/1, BB/I025263/1
University of Bristol
Russian Foundation for Basic Research	20-015-00496
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Mauritius Research Council	MC_UU_00011/1, MC_UU_00011/5

Keywords

ALSPAC
Breastfeeding
DNA methylation
EPIC
EWAS
NTR
Twins

Cohort Studies

Netherlands Twin Register (NTR)

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10.3390/nu11112804

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Odintsova, V. V., Hagenbeek, F. A., Suderman, M., Caramaschi, D., van Beijsterveldt, C. E. M., Kallsen, N. A., Ehli, E. A., Davies, G. E., Sukhikh, G. T., Fanos, V., Relton, C., Bartels, M., Boomsma, D. I., & van Dongen, J. (2019). DNA methylation signatures of breastfeeding in buccal cells collected in mid-childhood. Nutrients, 11(11), 1-26. Article 2804. https://doi.org/10.3390/nu11112804

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abstract = "Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized ('never' vs. 'ever'). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10-8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.",

keywords = "ALSPAC, Breastfeeding, DNA methylation, EPIC, EWAS, NTR, Twins",

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AU - Caramaschi, Doretta

AU - van Beijsterveldt, Catharina E.M.

AU - Kallsen, Noah A.

AU - Ehli, Erik A.

AU - Davies, Gareth E.

AU - Sukhikh, Gennady T.

AU - Fanos, Vassilios

AU - Relton, Caroline

AU - Bartels, Meike

AU - Boomsma, Dorret I.

AU - van Dongen, Jenny

PY - 2019/11/17

Y1 - 2019/11/17

N2 - Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized ('never' vs. 'ever'). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10-8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

AB - Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized ('never' vs. 'ever'). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10-8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

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DNA methylation signatures of breastfeeding in buccal cells collected in mid-childhood

Abstract

Funding

Keywords

Cohort Studies

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