Maternal Mediterranean diet in pregnancy and newborn DNA methylation: a meta-analysis in the PACE Consortium

ABSTRACT

Higher adherence to the Mediterranean diet during pregnancy is related to a lower risk of preterm birth and to better offspring cardiometabolic health. DNA methylation may be an underlying biological mechanism. We evaluated whether maternal adherence to the Mediterranean diet was associated with offspring cord blood DNA methylation.

We meta-analysed epigenome-wide association studies (EWAS) of maternal adherence to the Mediterranean diet during pregnancy and offspring cord blood DNA methylation in 2802 mother–child pairs from five cohorts. We calculated the relative Mediterranean diet (rMED) score with range 0–18 and an adjusted rMED excluding alcohol (rMEDp, range 0–16). DNA methylation was measured using Illumina 450K arrays. We used robust linear regression modelling adjusted for child sex, maternal education, age, smoking, body mass index, energy intake, batch, and cell types. We performed several functional analyses and examined the persistence of differential DNA methylation into childhood (4.5–7.8 y).

rMEDp was associated with cord blood DNA methylation at cg23757341 (0.064% increase in DNA methylation per 1-point increase in the rMEDp score, SE = 0.011, P = 2.41 × 10⁻⁸). This cytosine–phosphate–guanine (CpG) site maps to WNT5B, associated with adipogenesis and glycaemic phenotypes. We did not identify associations with childhood gene expression, nor did we find enriched biological pathways. The association did not persist into childhood.

In this meta-analysis, maternal adherence to the Mediterranean diet (excluding alcohol) during pregnancy was associated with cord blood DNA methylation level at cg23757341. Potential mediation of DNA methylation in associations with offspring health requires further study.

KEYWORDS:

• Epigenetics
• epigenome-wide association study
• DNA methylation
• Mediterranean diet
• prenatal diet
• maternal diet
• newborn
• cord blood

Acknowledgments

Cohort-specific acknowledgements are stated in the Supplementary File, all authors declare no conflicts of interest. LKK and JFF designed the research; LKK, SFB, AN, APS, CF, RF conducted cohort-specific EWAS; LKK meta-analysed the summary statistics from all cohort-specific EWAS, which was independently shadowed by SFB. LKK and JFF wrote the paper; LKK has primary responsibility for the final content. All authors critically reviewed and approved the final manuscript.

Authors’ contribution

• Leanne K. Küpers: Dr Küpers reports grants from European Joint Programming Initiative “A Healthy Diet for a Healthy Life during the conduct of the study.

• Sílvia Fernández-Barrés: Dr Fernández-Barrés has nothing to disclose.

• Aayah Nounu: Dr Nounu has nothing to disclose.

• Chloe Friedman: Ms Friedman has nothing to disclose.

• Ruby Fore: Ms Fore has nothing to disclose.

• Giulia Mancano: Dr Mancano reports grants from European Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ during the conduct of the study.

• Dana Dabelea: Dr Dabelea has nothing to disclose.

• Sheryl L. Rifas-Shiman: Dr Rifas-Shiman has nothing to disclose.

• Rosa H. Mulder: Dr Mulder reports grants from European Union’s Horizon 2020 research and innovation programme during the conduct of the study.

• Emily Oken: Dr Oken reports grants from the US National Institutes of Health during the conduct of the study.

• Laura Johnson: Dr Johnson reports grants from Alpro Foundation, grants from Danone baby nutrition, grants from Kellogg Europe, grants from UK research councils, grants from World Cancer Research Fund, outside the submitted work.

• Mariona Bustamante: Dr Bustamante has nothing to disclose.

• Vincent W.V. Jaddoe: Dr Jaddoe has nothing to disclose.

• Marie-France Hivert: Dr Hivert has nothing to disclose.

• Anne P. Starling: Dr Starling reports grants from National Institutes of Health during the conduct of the study.

• Jeanne H.M. de Vries: Dr de Vries has nothing to disclose.

• Gemma C. Sharp: Dr Sharp reports grants from EU Joint Programming Initiative JPI HDHL, grants from Medical Research Council (MRC) during the conduct of the study.

• Martine Vrijheid: Dr Vrijheid has nothing to disclose.

• Janine F. Felix: Dr Felix reports grants from European Union’s Horizon 2020 research and innovation programme, grants from European Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ during the conduct of the study.

Data sharing statement

Data described in the manuscript, code book, and analytic code will be made available upon request pending application and approval. Full EWAS results can be found at doi:10.5281/zenodo.5877662. Total files are approximately 46MB.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the Foundation for the National Institutes of Health [R01 HD034568, UH3 OD023286, R01 NR013945, R01 HL111108]; Joint Programming Initiative A healthy diet for a healthy life [529051023, MR/S036520/1, 529051022, MR/S036520/1, MR/S036520/1]; National Institute of Environmental Health Sciences [R00ES025817]; National institute of diabetes and digestive and kidney diseases [R01DK076648]; National Institutes of Health Office of the Director [UH3OD023248]; Horizon 2020 research and innovation [874739, 733206, 848158, 824989]; Medical Research Council [MR/S009310/1].