Meta-Analysis

. 2022 Apr;27(4):2126-2135.

doi: 10.1038/s41380-022-01441-w. Epub 2022 Feb 10.

Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills

Doretta Caramaschi^#^{1

2}, Alexander Neumann^#^{3

4}, Andres Cardenas⁵, Gwen Tindula⁶, Silvia Alemany^{7

8

9}, Lea Zillich¹⁰, Giancarlo Pesce¹¹, Jari M T Lahti¹², Alexandra Havdahl^{13

14}, Rosa Mulder^{3

15

16}, Janine F Felix^{15

16}, Henning Tiemeier³, Lea Sirignano¹⁰, Josef Frank¹⁰, Stephanie H Witt¹⁰, Marcella Rietschel¹⁰, Michael Deuschle¹⁷, Karen Huen⁶, Brenda Eskenazi¹⁸, Tabea Sarah Send¹⁷, Muriel Ferrer⁷, Maria Gilles¹⁷, Maria de Agostini¹⁹, Nour Baïz¹¹, Sheryl L Rifas-Shiman²⁰, Tuomas Kvist¹², Darina Czamara²¹, Samuli T Tuominen¹², Caroline L Relton¹³, Dheeraj Rai¹³, Stephanie J London²², Katri Räikkönen¹², Nina Holland⁶, Isabella Annesi-Maesano¹¹, Fabian Streit¹⁰, Marie-France Hivert²⁰, Emily Oken²⁰, Jordi Sunyer^{7

8

9

23}, Charlotte A M Cecil^{3

24

25}, Gemma Sharp¹³

Affiliations

¹ Medical Research Council Integrative Epidemiology Unit (MRC IEU), Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK. d.caramaschi@exeter.ac.uk.
² Department of Psychology, College of Life and Environmental Sciences, University of Exeter, Exeter, UK. d.caramaschi@exeter.ac.uk.
³ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
⁵ Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
⁶ Children's Environmental Health Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.
⁷ ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
⁸ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁹ CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain.
¹⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
¹¹ Epidemiology of Allergic and Respiratory Diseases Team (EPAR), Institute Pierre Louis of Epidemiology and Public Health, UMR-S 1136 INSERM and Sorbonne Université, Paris, France.
¹² Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹³ Medical Research Council Integrative Epidemiology Unit (MRC IEU), Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK.
¹⁴ Department of Mental Disorders, Norwegian Institute of Public Health and Nic Waals Institute of Lovisenberg Diaconal Hospital, Oslo, Norway.
¹⁵ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁶ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁷ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁸ Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California, Berkeley, CA, USA.
¹⁹ Inserm, Centre for Research in Epidemiology and StatisticS (CRESS), Research Team on Early Life Origins of Health (EAROH), Villejuif, France.
²⁰ Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
²¹ Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
²² National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
²³ Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
²⁴ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
²⁵ Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.

^# Contributed equally.

PMID: 35145228
PMCID: PMC9126809
DOI: 10.1038/s41380-022-01441-w

Meta-Analysis

Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills

Doretta Caramaschi et al. Mol Psychiatry. 2022 Apr.

. 2022 Apr;27(4):2126-2135.

doi: 10.1038/s41380-022-01441-w. Epub 2022 Feb 10.

Authors

Affiliations

¹ Medical Research Council Integrative Epidemiology Unit (MRC IEU), Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK. d.caramaschi@exeter.ac.uk.
² Department of Psychology, College of Life and Environmental Sciences, University of Exeter, Exeter, UK. d.caramaschi@exeter.ac.uk.
³ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁴ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
⁵ Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
⁶ Children's Environmental Health Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.
⁷ ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
⁸ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁹ CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain.
¹⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
¹¹ Epidemiology of Allergic and Respiratory Diseases Team (EPAR), Institute Pierre Louis of Epidemiology and Public Health, UMR-S 1136 INSERM and Sorbonne Université, Paris, France.
¹² Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹³ Medical Research Council Integrative Epidemiology Unit (MRC IEU), Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK.
¹⁴ Department of Mental Disorders, Norwegian Institute of Public Health and Nic Waals Institute of Lovisenberg Diaconal Hospital, Oslo, Norway.
¹⁵ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁶ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁷ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁸ Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California, Berkeley, CA, USA.
¹⁹ Inserm, Centre for Research in Epidemiology and StatisticS (CRESS), Research Team on Early Life Origins of Health (EAROH), Villejuif, France.
²⁰ Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
²¹ Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
²² National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
²³ Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
²⁴ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
²⁵ Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.

^# Contributed equally.

PMID: 35145228
PMCID: PMC9126809
DOI: 10.1038/s41380-022-01441-w

Abstract

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.

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Conflict of interest statement

MD served as PI in phase II and III studies of Johnson & Johnson, Lilly and Roche. He participated in advisory boards of Johnson & Johnson and received speaker fees from Mundipharma. GT received a Student/New Investigator Travel Award of $750.00 to attend and present at the 2019 Environmental Mutagenesis and Genomics Society (EMGS) meeting in Washington DC from September 19–23, 2019. All the other co-authors declare no competing interests.

Figures

**Fig. 1. Results from the meta-analysis of epigenome-wide association studies of cognitive skills in childhood and DNA methylation in cord blood.**
A–C QQ plots showing the observed vs expected probabilities per CpG site and λ index of genomic inflation. D–F Manhattan plots showing the −log10(p values) at each CpG site according to chromosome location. G–I Volcano plots showing the effect sizes (difference in IQ z-score units per change from 0 to 1 proportion methylated) and probability values for each CpG site. Models were adjusted for age at testing, sex, maternal age at delivery, maternal education, birth weight, gestational age, maternal smoking status during pregnancy, parity, batch covariates and cell proportions.

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Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills

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Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills

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