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 Guan; Xuehuo 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

doi:10.1186/s13148-023-01542-5

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

Clin Epigenetics. 2023 Sep 11;15(1):148. doi: 10.1186/s13148-023-01542-5.

Authors

Latha Kadalayil^{1

2}, Md Zahangir Alam^{2

3}, Cory Haley White⁴, Akram Ghantous⁵, Esther Walton^#⁶, Olena Gruzieva^{7

8}, Simon Kebede Merid⁸, Ashish Kumar⁹, Ritu P Roy^{10

11}, Olivia Solomon¹², Karen Huen¹², Brenda Eskenazi¹², Peter Rzehak¹³, Veit Grote¹³, Jean-Paul Langhendries¹⁴, Elvira Verduci¹⁵, Natalia Ferre¹⁶, Darek Gruszfeld¹⁷, Lu Gao¹⁸, Weihua Guan¹⁹, Xuehuo Zeng²⁰, Enrique F Schisterman²¹, John F Dou²², Kelly M Bakulski²², Jason I Feinberg^{23

24}, Munawar Hussain Soomro^{25

26}, Giancarlo Pesce²⁵, Nour Baiz²⁷, Elena Isaevska²⁸, Michelle Plusquin²⁹, Marina Vafeiadi³⁰, Theano Roumeliotaki³⁰, Sabine A S Langie^{31

32

33}, Arnout Standaert³¹, Catherine Allard³⁴, Patrice Perron³⁵, Luigi Bouchard^{36

37}, Evelien R van Meel^{38

39}, Janine F Felix^{38

40}, Vincent W V Jaddoe^{38

40}, Paul D Yousefi^{41

42}, Cecilia H Ramlau-Hansen⁴³, Caroline L Relton^{41

42}, Elmar W Tobi⁴⁴, Anne P Starling^{45

46

47}, Ivana V Yang^{46

48

49}, Maria Llambrich^{50

51

52}, Gillian Santorelli⁵³, Johanna Lepeule⁵⁴, Lucas A Salas^{50

55

56

57}, Mariona Bustamante^{50

51

52}, Susan L Ewart⁵⁸, Hongmei Zhang⁵⁹, Wilfried Karmaus⁵⁹, Stefan Röder⁶⁰, Ana Claudia Zenclussen⁶⁰, Jianping Jin⁶¹, Wenche Nystad⁶², Christian M Page^{63

64}, Maria Magnus⁶³, Dereje D Jima^{65

66}, Cathrine Hoyo^{65

67}, Rachel L Maguire^{67

68}, Tuomas Kvist⁶⁹, Darina Czamara⁷⁰, Katri Räikkönen⁶⁹, Tong Gong⁷¹, Vilhelmina Ullemar⁷¹, Sheryl L Rifas-Shiman⁷², Emily Oken^#⁷², Catarina Almqvist^#^{71

73}, Robert Karlsson⁷¹, Jari Lahti⁶⁹, Susan K Murphy⁶⁸, Siri E Håberg⁶³, Stephanie London⁷⁴, Gunda Herberth⁶⁰, Hasan Arshad^{1

75

76}, Jordi Sunyer^{50

51

52}, Regina Grazuleviciene⁷⁷, Dana Dabelea^{45

46

78}, Régine P M Steegers-Theunissen⁴⁴, Ellen A Nohr⁷⁹, Thorkild I A Sørensen^{80

81}, Liesbeth Duijts^{38

39

82}, Marie-France Hivert^{72

83}, Vera Nelen⁸⁴, Maja Popovic²⁸, Manolis Kogevinas⁵⁰, Tim S Nawrot^{29

85}, Zdenko Herceg⁵, Isabella Annesi-Maesano²⁷, M Daniele Fallin^{23

24}, Edwina Yeung⁸⁶, Carrie V Breton¹⁸, Berthold Koletzko¹³, Nina Holland⁸⁷, Joseph L Wiemels^{88

89}, Erik Melén^{9

90}, Gemma C Sharp^{41

91}, Matt J Silver^{92

93}, Faisal I Rezwan^#^{2

94}, John W Holloway^#^{95

96}

Affiliations

¹ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
² Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
³ Department of Computer Science and Engineering, Bangladesh University of Engineering and Technology, Dhaka, Bangladesh.
⁴ Merck Exploratory Science Center in Cambridge MA, Merck Research Laboratories, Cambridge, MA, 02141, USA.
⁵ Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France.
⁶ Department of Psychology, University of Bath, Bath, UK.
⁷ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ Centre for Occupational and Environmental Medicine, Region Stockholm, Sweden.
⁹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Helen Diller Family Comprehensive Cancer Center University of California, San Francisco, CA, 94143, USA.
¹¹ Computational Biology and Informatics Core, University of California, San Francisco, CA, 94143, USA.
¹² Children's Environmental Health Laboratory, University of California, Berkeley, CA, USA.
¹³ Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany.
¹⁴ CHC, St Vincent, Liège-Rocourt, Belgium.
¹⁵ Department of Pediatrics, Vittore Buzzi Children Hospital, University of Milan, Milan, Italy.
¹⁶ Pediatric Nutrition and Human Development Research Unit, Universitat Rovira i Virgili, IISPV, Reus, Spain.
¹⁷ Neonatal Department, Children's Memorial Health Institute, Warsaw, Poland.
¹⁸ Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁹ Division of Biostatistics, School of Public Health, University of Minnesota, A460 Mayo Building, MMC 303, 420 Delaware St. SE, Minneapolis, MN, 55455, USA.
²⁰ Glotech, Inc., Rockville, MD, USA.
²¹ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, 423 Guardian Drive, Philadelphia, PA, 19104, USA.
²² Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, USA.
²³ Wendy Klag Center for Autism and Developmental Disabilities Johns Hopkins University, Baltimore, MD, USA.
²⁴ Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
²⁵ Sorbonne Université and INSERM, Epidemiology of Allergic and Respiratory Diseases Department, Pierre Louis Institute of Epidemiology and Public Health (IPLESP UMRS 1136), Saint-Antoine Medical School, Paris Cedex 12, France.
²⁶ Department of Community Medicine and Public Health, SMBB Medical University, Larkana, Pakistan.
²⁷ Institut Desbrest de Santé Publique (IDESP), INSERM and Montpellier University, Montpellier, France.
²⁸ Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, CPO Piemonte, Italy.
²⁹ Center for Environmental Sciences, University of Hasselt, 3590, Diepenbeek, Belgium.
³⁰ Department of Social Medicine, School of Medicine, University of Crete, Heraklion, Greece.
³¹ Unit Health, Flemish Institute for Technological Research (VITO), Mol, Belgium.
³² Faculty of Sciences, Hasselt University, Diepenbeek, Belgium.
³³ Department of Pharmacology and Toxicology, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Limburg, The Netherlands.
³⁴ Centre de Recherche du Centre Hospitalier de l'Universite de Sherbrooke, Sherbrooke, Canada.
³⁵ Department of Medicine, Universite de Sherbrooke, Sherbrooke, Canada.
³⁶ Department of Biochemistry and Functional Genomics, Universite de Sherbrooke, Sherbrooke, Canada.
³⁷ Clinical Department of Laboratory Medicine, Centre intégré universitaire de santé et de services sociaux (CIUSSS) du Saguenay-Lac-Saint-Jean - Hôpital de Chicoutimi, Chicoutimi, Canada.
³⁸ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
³⁹ Division of Respiratory Medicine and Allergology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴⁰ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴¹ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁴² Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
⁴³ Department of Public Health, Aarhus University, Aarhus, Denmark.
⁴⁴ Periconceptional Epidemiology, Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
⁴⁵ Life Course Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴⁶ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴⁷ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁸ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴⁹ Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
⁵⁰ Institute for Global Health (ISGlobal), Barcelona, Spain.
⁵¹ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵² CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
⁵³ Bradford Institute for Health Research, Bradford, UK.
⁵⁴ Institute for Advanced Biosciences, University Grenoble-Alpes, INSERM, CNRS, Grenoble, France.
⁵⁵ Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
⁵⁶ Center for Molecular Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA.
⁵⁷ Children's Environmental Health and Disease Prevention Research Center at Dartmouth, Lebanon, NH, USA.
⁵⁸ Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
⁵⁹ Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, USA.
⁶⁰ Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.
⁶¹ 2530 Meridian Pkwy, Suite 200, Durham, NC 27713, USA.
⁶² Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway.
⁶³ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁶⁴ Section for Statistics and Data Science, Department of Mathematics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
⁶⁵ Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA.
⁶⁶ Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
⁶⁷ Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
⁶⁸ Department of Obstetrics and Gynaecology, Duke University Medical Center, Durham, NC, USA.
⁶⁹ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
⁷⁰ Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, 80804, Munich, Germany.
⁷¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁷² Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, USA.
⁷³ Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
⁷⁴ Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, NC, 27709, USA.
⁷⁵ David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.
⁷⁶ NIHR Southampton Biomedical Research Centre, Southampton General Hospital, Southampton, UK.
⁷⁷ Department of Environmental Science, Vytautas Magnus University, 44248, Kaunas, Lithuania.
⁷⁸ Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁷⁹ Department of Clinical Research, Odense Universitetshospital, Odense, Denmark.
⁸⁰ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸¹ Department Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸² Division of Neonatology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁸³ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
⁸⁴ Provincial Institute for Hygiene, Antwerp, Belgium.
⁸⁵ Department of Public Health and Primary Care, Leuven University, Louvain, Belgium.
⁸⁶ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Dr, MSC 7004, Bethesda, MD, USA.
⁸⁷ Children's Environmental Health Laboratory, CERCH, Berkeley Public Health, University of California, 2121 Berkeley Way #5216, Berkeley, CA, 94720, USA.
⁸⁸ Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, 90033, USA.
⁸⁹ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
⁹⁰ Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.
⁹¹ School of Psychology, University of Exeter, Exeter, UK.
⁹² Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia.
⁹³ Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, London, UK.
⁹⁴ Department of Computer Science, Aberystwyth University, Aberystwyth, Ceredigion, UK.
⁹⁵ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK. [email protected].
⁹⁶ NIHR Southampton Biomedical Research Centre, Southampton General Hospital, Southampton, UK. [email protected].

^# Contributed equally.

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.

Keywords: Birth season; DNA methylation; Differentially methylated regions (DMR); Latitude; Meta-analysis; PACE.

Publication types

Meta-Analysis

MeSH terms

Asthma*
Carcinogenesis
Child
Child, Preschool
DNA Methylation*
Humans
Infant
Infant, Newborn
Inflammation
Seasons

Abstract

Publication types

MeSH terms

Grants and funding