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DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake

DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake
DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake
Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human Methylation EPIC array, we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women’s Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p ≤ 6.45×10−8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195 g (95%CI: −241, −149 g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin-releasing hormone-binding protein (CRHBP). Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p = 1.37×10−255), maternal smoking (7.71%, p = 1.50 x 10−57) and maternal plasma folate levels during pregnancy (0.33%, p = 0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs
Birthweight, dna methylation, early life environment, pregnancy
1559-2294
Antoun, Elie
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Titcombe, Philip
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Dalrymple, Kathryn V.
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Kitaba, Negusse
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Barton, Sheila
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Flynn, A.C.
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Murray, Robert
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Garratt, Emma
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Seed, Paul T.
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White, Sara L.
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Cooper, Cyrus
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Inskip, Hazel
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Hanson, Mark
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Poston, L.
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Godfrey, Keith
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Lillycrop, Karen
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Antoun, Elie
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Titcombe, Philip
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Dalrymple, Kathryn V.
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Kitaba, Negusse
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Barton, Sheila
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Flynn, A.C.
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Murray, Robert
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Garratt, Emma
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Seed, Paul T.
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White, Sara L.
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Cooper, Cyrus
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Inskip, Hazel
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Hanson, Mark
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Poston, L.
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Godfrey, Keith
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Lillycrop, Karen
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Antoun, Elie, Titcombe, Philip, Dalrymple, Kathryn V., Kitaba, Negusse, Barton, Sheila, Flynn, A.C., Murray, Robert, Garratt, Emma, Seed, Paul T., White, Sara L., Cooper, Cyrus, Inskip, Hazel, Hanson, Mark, Poston, L., Godfrey, Keith and Lillycrop, Karen (2021) DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake. Epigenetics. (doi:10.1080/15592294.2021.1908706).

Record type: Article

Abstract

Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human Methylation EPIC array, we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women’s Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p ≤ 6.45×10−8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195 g (95%CI: −241, −149 g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin-releasing hormone-binding protein (CRHBP). Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p = 1.37×10−255), maternal smoking (7.71%, p = 1.50 x 10−57) and maternal plasma folate levels during pregnancy (0.33%, p = 0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs

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More information

Accepted/In Press date: 17 March 2021
e-pub ahead of print date: 30 March 2021
Keywords: Birthweight, dna methylation, early life environment, pregnancy

Identifiers

Local EPrints ID: 450029
URI: http://eprints.soton.ac.uk/id/eprint/450029
ISSN: 1559-2294
PURE UUID: 7fb07108-3327-42d8-99b2-82497423e7ee
ORCID for Philip Titcombe: ORCID iD orcid.org/0000-0002-7797-8571
ORCID for Negusse Kitaba: ORCID iD orcid.org/0000-0001-7518-9096
ORCID for Sheila Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for Emma Garratt: ORCID iD orcid.org/0000-0001-5268-4203
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Hazel Inskip: ORCID iD orcid.org/0000-0001-8897-1749
ORCID for Mark Hanson: ORCID iD orcid.org/0000-0002-6907-613X
ORCID for Keith Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Karen Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489

Catalogue record

Date deposited: 06 Jul 2021 16:31
Last modified: 26 Nov 2021 03:10

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Contributors

Author: Elie Antoun
Author: Philip Titcombe ORCID iD
Author: Kathryn V. Dalrymple
Author: Negusse Kitaba ORCID iD
Author: Sheila Barton ORCID iD
Author: A.C. Flynn
Author: Robert Murray
Author: Emma Garratt ORCID iD
Author: Paul T. Seed
Author: Sara L. White
Author: Cyrus Cooper ORCID iD
Author: Hazel Inskip ORCID iD
Author: Mark Hanson ORCID iD
Author: L. Poston
Author: Keith Godfrey ORCID iD
Author: Karen Lillycrop ORCID iD

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