Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude
Authors: Kadalayil Latha , Alam Md. Zahangir , White Cory Haley , Ghantous Akram , Walton Esther , Gruzieva Olena , Merid Simon Kebede , Kumar Ashish , Roy Ritu P. , Solomon Olivia , Huen Karen , Eskenazi Brenda , Rzehak Peter , Grote Veit , Langhendries Jean-Paul , Verduci Elvira , Ferre Natalia , Gruszfeld Darek , Gao Lu , Guan Weihua , Zeng Xuehuo , Schisterman Enrique F. , Dou John F. , Bakulski Kelly M. , Feinberg Jason I. , Soomro Munawar Hussain , Pesce Giancarlo , Baiz Nour , Isaevska Elena , Plusquin Michelle , Vafeiadi Marina , Roumeliotaki Theano , Langie Sabine A. S. , Standaert Arnout , Allard Catherine , Perron Patrice , Bouchard Luigi , van Meel Evelien R. , Felix Janine F. , Jaddoe Vincent W. V. , Yousefi Paul D. , Ramlau-Hansen Cecilia H. , Relton Caroline L. , Tobi Elmar W. , Starling Anne P. , Yang Ivana V. , Llambrich Maria , Santorelli Gillian , Lepeule Johanna , Salas Lucas A. , Bustamante Mariona , Ewart Susan L. , Zhang Hongmei , Karmaus Wilfried , Röder Stefan , Zenclussen Ana Claudia , Jin Jianping , Nystad Wenche , Page Christian M. , Magnus Maria , Jima Dereje D. , Hoyo Cathrine , Maguire Rachel L. , Kvist Tuomas , Czamara Darina , Räikkönen Katri , Gong Tong , Ullemar Vilhelmina , Rifas-Shiman Sheryl L. , Oken Emily , Almqvist Catarina , Karlsson Robert , Lahti Jari , Murphy Susan K. , Håberg Siri E. , London Stephanie , Herberth Gunda , Arshad Hasan , Sunyer Jordi , Grazuleviciene Regina , Dabelea Dana , Steegers-Theunissen Régine P. M. , Nohr Ellen A. , Sørensen Thorkild I. A. , Duijts Liesbeth , Hivert Marie-France , Nelen Vera , Popovic Maja , Kogevinas Manolis , Nawrot Tim S. , Herceg Zdenko , Annesi-Maesano Isabella , Fallin M. Daniele , Yeung Edwina , Breton Carrie V. , Koletzko Berthold , Holland Nina , Wiemels Joseph L. , Melén Erik , Sharp Gemma C. , Silver Matt J. , Rezwan Faisal I. , Holloway John W. 
Published: September 2023

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-adjustedpvalues < 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.