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Paternal DNA methylation may be associated with gestational age at birth

Paternal DNA methylation may be associated with gestational age at birth
Paternal DNA methylation may be associated with gestational age at birth

Background: How epigenetic modifications of DNA are associated with gestational age at birth is not fully understood. We investigated potential effects of differential paternal DNA methylation (DNAm) on offspring gestational age at birth by conducting an epigenome-wide search for cytosine-phosphate-guanine (CpG) sites. Methods: Study participants in this study consist of male cohort members or partners of the F1-generation of the Isle of Wight Birth Cohort (IoWBC). DNAm levels in peripheral blood from F1-fathers (n = 92) collected around pregnancy of their spouses were analyzed using the Illumina 450K array. A 5-step statistical analysis was performed. First, a training-testing screening approach was applied to select CpG sites that are potentially associated with gestational age at birth. Second, functional enrichment analysis was employed to identify biological processes. Third, by centralizing on biologically informative genes, Cox proportional hazards models were used to assess the hazard ratios of individual paternal CpGs on gestational age adjusting for confounders. Fourth, to assess the validity of our results, we compared our CpG-gestational age correlations within a Born into Life Study in Sweden (n = 15). Finally, we investigated the correlation between the detected CpGs and differential gene expression in F2 cord blood in the IoWBC. Results: Analysis of DNAm of fathers collected around their partner’s pregnancy identified 216 CpG sites significantly associated with gestational age at birth. Functional enrichment pathways analyses of the annotated genes revealed 2 biological pathways significantly related to cell-cell membrane adhesion molecules. Differential methylation of 9 cell membrane adhesion pathway-related CpGs were significantly associated with gestational age at birth after adjustment for confounders. The replication sample showed correlation coefficients of 2 pathway-related CpGs with gestational age at birth within 95% confidence intervals of correlation coefficients in IoWBC. Finally, CpG sites of protocadherin (PCDH) gene clusters were associated with gene expression of PCDH in F2 cord blood. Conclusions: Our findings suggest that differential paternal DNAm may affect gestational age at birth through cell-cell membrane adhesion molecules. The results are novel but require future replication in a larger cohort.

Epigenetics, gestational age, paternal DNA methylation
2516-8657
Luo, Rui
fd323ddc-9115-415e-87d9-594bfde6c90d
Mukherjee, Nandini
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Chen, Su
d92fd66e-496f-4bb8-ab1c-625f3addbf6f
Jiang, Yu
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Arshad, Syed
917e246d-2e60-472f-8d30-94b01ef28958
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Hedman, Anna
1a78c62e-8caf-4b18-b275-3a991a5e41f6
Gruzieva, Olena
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Andolf, Ellika
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Pershagen, Goran
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Almqvist, Catarina
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Karmaus, Wilfried Jj
af0a33bd-1556-477c-8d72-aa3c40c92f27
Luo, Rui
fd323ddc-9115-415e-87d9-594bfde6c90d
Mukherjee, Nandini
f64f02d6-2fd0-40db-88ee-5f85b59b8e0b
Chen, Su
d92fd66e-496f-4bb8-ab1c-625f3addbf6f
Jiang, Yu
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Arshad, Syed
917e246d-2e60-472f-8d30-94b01ef28958
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Hedman, Anna
1a78c62e-8caf-4b18-b275-3a991a5e41f6
Gruzieva, Olena
0865d16b-2fdc-4e58-b834-a9fd22283ca5
Andolf, Ellika
218974e3-872a-4ee9-9ff0-4721d1dc09a8
Pershagen, Goran
601a5ea0-924c-4e82-8037-b282d36c3439
Almqvist, Catarina
68bd5bec-1e94-4252-96b8-485c8308561c
Karmaus, Wilfried Jj
af0a33bd-1556-477c-8d72-aa3c40c92f27

Luo, Rui, Mukherjee, Nandini, Chen, Su, Jiang, Yu, Arshad, Syed, Holloway, John W, Hedman, Anna, Gruzieva, Olena, Andolf, Ellika, Pershagen, Goran, Almqvist, Catarina and Karmaus, Wilfried Jj (2020) Paternal DNA methylation may be associated with gestational age at birth. Epigenetics Insights, 13. (doi:10.1177/2516865720930701).

Record type: Article

Abstract

Background: How epigenetic modifications of DNA are associated with gestational age at birth is not fully understood. We investigated potential effects of differential paternal DNA methylation (DNAm) on offspring gestational age at birth by conducting an epigenome-wide search for cytosine-phosphate-guanine (CpG) sites. Methods: Study participants in this study consist of male cohort members or partners of the F1-generation of the Isle of Wight Birth Cohort (IoWBC). DNAm levels in peripheral blood from F1-fathers (n = 92) collected around pregnancy of their spouses were analyzed using the Illumina 450K array. A 5-step statistical analysis was performed. First, a training-testing screening approach was applied to select CpG sites that are potentially associated with gestational age at birth. Second, functional enrichment analysis was employed to identify biological processes. Third, by centralizing on biologically informative genes, Cox proportional hazards models were used to assess the hazard ratios of individual paternal CpGs on gestational age adjusting for confounders. Fourth, to assess the validity of our results, we compared our CpG-gestational age correlations within a Born into Life Study in Sweden (n = 15). Finally, we investigated the correlation between the detected CpGs and differential gene expression in F2 cord blood in the IoWBC. Results: Analysis of DNAm of fathers collected around their partner’s pregnancy identified 216 CpG sites significantly associated with gestational age at birth. Functional enrichment pathways analyses of the annotated genes revealed 2 biological pathways significantly related to cell-cell membrane adhesion molecules. Differential methylation of 9 cell membrane adhesion pathway-related CpGs were significantly associated with gestational age at birth after adjustment for confounders. The replication sample showed correlation coefficients of 2 pathway-related CpGs with gestational age at birth within 95% confidence intervals of correlation coefficients in IoWBC. Finally, CpG sites of protocadherin (PCDH) gene clusters were associated with gene expression of PCDH in F2 cord blood. Conclusions: Our findings suggest that differential paternal DNAm may affect gestational age at birth through cell-cell membrane adhesion molecules. The results are novel but require future replication in a larger cohort.

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More information

Accepted/In Press date: 9 May 2020
Published date: 10 September 2020
Additional Information: © The Author(s) 2020.
Keywords: Epigenetics, gestational age, paternal DNA methylation

Identifiers

Local EPrints ID: 445619
URI: http://eprints.soton.ac.uk/id/eprint/445619
ISSN: 2516-8657
PURE UUID: 070f1329-28b6-4e60-8dde-6f948d9a0734
ORCID for John W Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 18 Dec 2020 17:31
Last modified: 26 Nov 2021 02:40

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Contributors

Author: Rui Luo
Author: Nandini Mukherjee
Author: Su Chen
Author: Yu Jiang
Author: Syed Arshad
Author: John W Holloway ORCID iD
Author: Anna Hedman
Author: Olena Gruzieva
Author: Ellika Andolf
Author: Goran Pershagen
Author: Catarina Almqvist
Author: Wilfried Jj Karmaus

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