Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Latha Kadalayil, Md. Zahangir Alam, Cory Haley White, Akram Ghantous, Esther Walton, Olena Gruzieva, Simon Kebede Merid, Ashish Kumar, Ritu P. Roy, Olivia Solomon, Karen Huen, Brenda Eskenazi, Peter Rzehak, Veit Grote, Jean-Paul Langhendries, Elvira Verduci, Natalia Ferre, Darek Gruszfeld, Lu Gao, Weihua GuanXuehuo Zeng, Enrique F. Schisterman, John F. Dou, Kelly M. Bakulski, Jason I. Feinberg, Munawar Hussain Soomro, Giancarlo Pesce, Nour Baiz, Elena Isaevska, Michelle Plusquin, Marina Vafeiadi, Theano Roumeliotaki, Sabine A. S. Langie, Arnout Standaert, Catherine Allard, Patrice Perron, Luigi Bouchard, Evelien R. van Meel, Janine F. Felix, Vincent W. V. Jaddoe, Paul D. Yousefi, Cecilia H. Ramlau-Hansen, Caroline L. Relton, Elmar W. Tobi, Anne P. Starling, Ivana V. Yang, Maria Llambrich, Gillian Santorelli, Johanna Lepeule, Lucas A. Salas, Mariona Bustamante, Susan L. Ewart, Hongmei Zhang, Wilfried Karmaus, Stefan Röder, Ana Claudia Zenclussen, Jianping Jin, Wenche Nystad, Christian M. Page, Maria Magnus, Dereje D. Jima, Cathrine Hoyo, Rachel L. Maguire, Tuomas Kvist, Darina Czamara, Katri Räikkönen, Tong Gong, Vilhelmina Ullemar, Sheryl L. Rifas-Shiman, Emily Oken, Catarina Almqvist, Robert Karlsson, Jari Lahti, Susan K. Murphy, Siri E. Håberg, Stephanie London, Gunda Herberth, Hasan Arshad, Jordi Sunyer, Regina Grazuleviciene, Dana Dabelea, Régine P. M. Steegers-Theunissen, Ellen A. Nohr, Thorkild I. A. Sørensen, Liesbeth Duijts, Marie-France Hivert, Vera Nelen, Maja Popovic, Manolis Kogevinas, Tim S. Nawrot, Zdenko Herceg, Isabella Annesi-Maesano, M. Daniele Fallin, Edwina Yeung, Carrie V. Breton, Berthold Koletzko, Nina Holland, Joseph L. Wiemels, Erik Melén, Gemma C. Sharp, Matt J. Silver, Faisal I. Rezwan, John W. Holloway*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Background
Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.

Methods
We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1–11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.

Results
We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).

Conclusions
In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.
Original languageEnglish
Article number148
Number of pages23
JournalClinical epigenetics
Volume15
Issue number1
Early online date11 Sept 2023
DOIs
Publication statusPublished - 31 Dec 2023

Keywords

  • Meta-analysis
  • PACE
  • Differentially methylated regions (DMR)
  • Birth season
  • Latitude
  • DNA methylation
  • Humans
  • Child, Preschool
  • Infant
  • Inflammation
  • Carcinogenesis
  • Asthma
  • DNA Methylation
  • Seasons
  • Child
  • Infant, Newborn

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