Genetic Susceptibility to Neurodevelopmental Conditions Is Associated With Neonatal DNA Methylation Patterns in the General Population: an individual participant data meta-analysis

Isabel K Schuurmans; Dinka Smajlagic; Vilte Baltramonaityte; Anni L K Malmberg; Alexander Neumann; Nicole Creasey; Janine F Felix; Henning Tiemeier; Jean-Baptiste Pingault; Darina Czamara; Katri Raïkkönen; Chistian Magnus Page; Robert Lyle; Alexandra Havdahl; Jari Lahti; Esther Walton; Mona Bekkhus; Charlotte A M Cecil

doi:10.1016/j.biopsych.2025.09.005

Genetic Susceptibility to Neurodevelopmental Conditions Is Associated With Neonatal DNA Methylation Patterns in the General Population: an individual participant data meta-analysis

Isabel K Schuurmans, Dinka Smajlagic, Vilte Baltramonaityte, Anni L K Malmberg, Alexander Neumann, Nicole Creasey, Janine F Felix, Henning Tiemeier, Jean-Baptiste Pingault, Darina Czamara, Katri Raïkkönen, Chistian Magnus Page, Robert Lyle, Alexandra Havdahl, Jari Lahti, Esther Walton, Mona Bekkhus, Charlotte A M Cecil

Research output: Contribution to journal › Article › peer-review

Abstract

Background Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in fetal neurodevelopment. Epigenetic processes, such as DNA methylation (DNAm), are considered a key pathway of interest. However, it is unclear whether 1) genetic susceptibility to neurodevelopmental conditions (NDCs) is associated with DNAm patterns already at birth, 2) DNAm patterns are unique or shared across conditions, and 3) neonatal DNAm patterns can be leveraged to enhance genetic prediction of neurodevelopmental outcomes. Methods We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and SCZ (measured with polygenic scores [PGSs]) and cord blood DNAm in 4 European population–based cohorts ( n _pooled = 5802; 50.2% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Furthermore, we built methylation profile scores for each PGS to test incremental variance explained over genetic data alone in 130 developmental outcomes from birth to 14 years. Results In probe-level analyses, the SCZ PGS was associated with neonatal DNAm at 246 loci ( p < 9 × 10 ⁻⁸), predominantly in the major histocompatibility complex, supporting an early-origins perspective on SCZ. Functional characterization confirmed strong genetic effects, blood-brain concordance, and enrichment for immune-related pathways. Eight loci were identified for the ASD PGS (mapping to FDFT1 and MFHAS1 ) and none for the ADHD PGS. Differentially methylated regions were detected across PGSs (130–166 regions). Overall, DNAm signals were largely distinct between conditions. Incorporating neonatal DNAm data in genetic prediction models nominally increased the explained variance for several cognitive and motor outcomes. Conclusions Genetic susceptibility to NDCs, particularly SCZ, is detectable in cord blood DNAm in the general population.

Original language	English
Journal	Biological Psychiatry
Early online date	22 Sept 2025
DOIs	https://doi.org/10.1016/j.biopsych.2025.09.005
Publication status	E-pub ahead of print - 22 Sept 2025

Acknowledgements

We declare this article has been posted as a preprint on the medRxiv server. The Generation R Study is conducted by Erasmus MC, University Medical Center Rotterdam in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The generation and management of the Illumina 450K methylation array data (EWAS data) for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. We thank Mr. Michael Verbiest, Ms. Mila Jhamai, Ms. Sarah Higgins, Mr. Marijn Verkerk and Dr. Lisette Stolk for their help in creating the EWAS database. We thank Dr. A. Teumer for his work on the quality control and normalization scripts. We also thank all the research nurses, research assistants, and laboratory personnel involved in the PREDO study. We are also extremely grateful to all the families who took part in the ALSPAC study, as well as for the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. We thank all the children and their parents for participation. We are grateful to all the participating families in Norway who take part in this on-going cohort study, MoBa. Finally, we would like to thank prof. dr. Roel Ophoff for his helpful input on the study.
The general design of the Generation R Study is made possible by financial support from Erasmus MC, Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development and the Ministry of Health, Welfare and Sport. The EWAS data were funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a grant from the National Institute of Child and Human Development (R01HD068437).
The PREDO study has received funding from the Academy of Finland, EraNet, EVO and VTR (special state subsidy for health science research), University of Helsinki Research Funds, the Signe and Ane Gyllenberg foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Jane and Aatos Erkko Foundation, the Novo Nordisk Foundation, the Päivikki and Sakari Sohlberg Foundation, Sigrid Juselius Foundation, the Sir Jules Thorn Charitable Trust, and , and the HiLife Fellows Programme 2023-25.
Core support for ALSPAC was provided by the UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. This publication is the work of the authors, and they will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (https://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). EW also received funding from the National Institute of Mental Health of the National Institutes of Health (award number R01MH113930) and from UK Research and Innovation (UKRI) under the UK government’s Horizon Europe / ERC Frontier Research Guarantee [BrainHealth, grant number EP/Y015037/1].
The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Versjon 6.9 3 Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities.

Funding

This project received funding from the European Union’s Horizon 2020 research and innovation programme (733206, LIFECYCLE; 848158, EarlyCause). The work of C.A.M.C. is supported the European Union’s HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529; HappyMums, grant agreement No 101057390) and the European Research Council (TEMPO; grant agreement No 101039672). This research was conducted while CAMC was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. The work of AN is also supported by the European Union’s HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529) and the European Research Council (TEMPO; grant agreement No 101039672). JBP and NC are supported by the ERC under the European Union’s Horizon 2020 research and innovation programme (iRISK; grant agreement No 863981). The work of AH is supported by the European Union’s HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529), the Research Council of Norway (#336085), and the South-Eastern Norway Regional Health Authority (#2020022; #2022029).

Keywords

DNA methylation
Epigenetics
Genetic susceptibility
Neurodevelopmental conditions
Population-based
Schizophrenia

ASJC Scopus subject areas

Biological Psychiatry

Access to Document

10.1016/j.biopsych.2025.09.005Licence: CC BY

Cite this

Schuurmans, I. K., Smajlagic, D., Baltramonaityte, V., Malmberg, A. L. K., Neumann, A., Creasey, N., Felix, J. F., Tiemeier, H., Pingault, J.-B., Czamara, D., Raïkkönen, K., Page, C. M., Lyle, R., Havdahl, A., Lahti, J., Walton, E., Bekkhus, M., & Cecil, C. A. M. (2025). Genetic Susceptibility to Neurodevelopmental Conditions Is Associated With Neonatal DNA Methylation Patterns in the General Population: an individual participant data meta-analysis. Biological Psychiatry. Advance online publication. https://doi.org/10.1016/j.biopsych.2025.09.005

Schuurmans, IK, Smajlagic, D, Baltramonaityte, V, Malmberg, ALK, Neumann, A, Creasey, N, Felix, JF, Tiemeier, H, Pingault, J-B, Czamara, D, Raïkkönen, K, Page, CM, Lyle, R, Havdahl, A, Lahti, J, Walton, E, Bekkhus, M & Cecil, CAM 2025, 'Genetic Susceptibility to Neurodevelopmental Conditions Is Associated With Neonatal DNA Methylation Patterns in the General Population: an individual participant data meta-analysis', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2025.09.005

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title = "Genetic Susceptibility to Neurodevelopmental Conditions Is Associated With Neonatal DNA Methylation Patterns in the General Population: an individual participant data meta-analysis",

abstract = "Background Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in fetal neurodevelopment. Epigenetic processes, such as DNA methylation (DNAm), are considered a key pathway of interest. However, it is unclear whether 1) genetic susceptibility to neurodevelopmental conditions (NDCs) is associated with DNAm patterns already at birth, 2) DNAm patterns are unique or shared across conditions, and 3) neonatal DNAm patterns can be leveraged to enhance genetic prediction of neurodevelopmental outcomes. Methods We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and SCZ (measured with polygenic scores [PGSs]) and cord blood DNAm in 4 European population–based cohorts ( n pooled = 5802; 50.2\% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Furthermore, we built methylation profile scores for each PGS to test incremental variance explained over genetic data alone in 130 developmental outcomes from birth to 14 years. Results In probe-level analyses, the SCZ PGS was associated with neonatal DNAm at 246 loci ( p < 9 × 10 −8), predominantly in the major histocompatibility complex, supporting an early-origins perspective on SCZ. Functional characterization confirmed strong genetic effects, blood-brain concordance, and enrichment for immune-related pathways. Eight loci were identified for the ASD PGS (mapping to FDFT1 and MFHAS1 ) and none for the ADHD PGS. Differentially methylated regions were detected across PGSs (130–166 regions). Overall, DNAm signals were largely distinct between conditions. Incorporating neonatal DNAm data in genetic prediction models nominally increased the explained variance for several cognitive and motor outcomes. Conclusions Genetic susceptibility to NDCs, particularly SCZ, is detectable in cord blood DNAm in the general population.",

keywords = "DNA methylation, Epigenetics, Genetic susceptibility, Neurodevelopmental conditions, Population-based, Schizophrenia",

author = "Schuurmans, \{Isabel K\} and Dinka Smajlagic and Vilte Baltramonaityte and Malmberg, \{Anni L K\} and Alexander Neumann and Nicole Creasey and Felix, \{Janine F\} and Henning Tiemeier and Jean-Baptiste Pingault and Darina Czamara and Katri Ra{\"i}kk{\"o}nen and Page, \{Chistian Magnus\} and Robert Lyle and Alexandra Havdahl and Jari Lahti and Esther Walton and Mona Bekkhus and Cecil, \{Charlotte A M\}",

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T1 - Genetic Susceptibility to Neurodevelopmental Conditions Is Associated With Neonatal DNA Methylation Patterns in the General Population

T2 - an individual participant data meta-analysis

AU - Schuurmans, Isabel K

AU - Smajlagic, Dinka

AU - Baltramonaityte, Vilte

AU - Malmberg, Anni L K

AU - Neumann, Alexander

AU - Creasey, Nicole

AU - Felix, Janine F

AU - Tiemeier, Henning

AU - Pingault, Jean-Baptiste

AU - Czamara, Darina

AU - Raïkkönen, Katri

AU - Page, Chistian Magnus

AU - Lyle, Robert

AU - Havdahl, Alexandra

AU - Lahti, Jari

AU - Walton, Esther

AU - Bekkhus, Mona

AU - Cecil, Charlotte A M

PY - 2025/9/22

Y1 - 2025/9/22

N2 - Background Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in fetal neurodevelopment. Epigenetic processes, such as DNA methylation (DNAm), are considered a key pathway of interest. However, it is unclear whether 1) genetic susceptibility to neurodevelopmental conditions (NDCs) is associated with DNAm patterns already at birth, 2) DNAm patterns are unique or shared across conditions, and 3) neonatal DNAm patterns can be leveraged to enhance genetic prediction of neurodevelopmental outcomes. Methods We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and SCZ (measured with polygenic scores [PGSs]) and cord blood DNAm in 4 European population–based cohorts ( n pooled = 5802; 50.2% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Furthermore, we built methylation profile scores for each PGS to test incremental variance explained over genetic data alone in 130 developmental outcomes from birth to 14 years. Results In probe-level analyses, the SCZ PGS was associated with neonatal DNAm at 246 loci ( p < 9 × 10 −8), predominantly in the major histocompatibility complex, supporting an early-origins perspective on SCZ. Functional characterization confirmed strong genetic effects, blood-brain concordance, and enrichment for immune-related pathways. Eight loci were identified for the ASD PGS (mapping to FDFT1 and MFHAS1 ) and none for the ADHD PGS. Differentially methylated regions were detected across PGSs (130–166 regions). Overall, DNAm signals were largely distinct between conditions. Incorporating neonatal DNAm data in genetic prediction models nominally increased the explained variance for several cognitive and motor outcomes. Conclusions Genetic susceptibility to NDCs, particularly SCZ, is detectable in cord blood DNAm in the general population.

AB - Background Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in fetal neurodevelopment. Epigenetic processes, such as DNA methylation (DNAm), are considered a key pathway of interest. However, it is unclear whether 1) genetic susceptibility to neurodevelopmental conditions (NDCs) is associated with DNAm patterns already at birth, 2) DNAm patterns are unique or shared across conditions, and 3) neonatal DNAm patterns can be leveraged to enhance genetic prediction of neurodevelopmental outcomes. Methods We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and SCZ (measured with polygenic scores [PGSs]) and cord blood DNAm in 4 European population–based cohorts ( n pooled = 5802; 50.2% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Furthermore, we built methylation profile scores for each PGS to test incremental variance explained over genetic data alone in 130 developmental outcomes from birth to 14 years. Results In probe-level analyses, the SCZ PGS was associated with neonatal DNAm at 246 loci ( p < 9 × 10 −8), predominantly in the major histocompatibility complex, supporting an early-origins perspective on SCZ. Functional characterization confirmed strong genetic effects, blood-brain concordance, and enrichment for immune-related pathways. Eight loci were identified for the ASD PGS (mapping to FDFT1 and MFHAS1 ) and none for the ADHD PGS. Differentially methylated regions were detected across PGSs (130–166 regions). Overall, DNAm signals were largely distinct between conditions. Incorporating neonatal DNAm data in genetic prediction models nominally increased the explained variance for several cognitive and motor outcomes. Conclusions Genetic susceptibility to NDCs, particularly SCZ, is detectable in cord blood DNAm in the general population.

KW - DNA methylation

KW - Epigenetics

KW - Genetic susceptibility

KW - Neurodevelopmental conditions

KW - Population-based

KW - Schizophrenia

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DO - 10.1016/j.biopsych.2025.09.005

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JF - Biological Psychiatry

ER -

Genetic Susceptibility to Neurodevelopmental Conditions Is Associated With Neonatal DNA Methylation Patterns in the General Population: an individual participant data meta-analysis

Abstract

Acknowledgements

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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BrainHealth - Decoding life course pathways of mental ageing - Frontier Research Guarantee

Cite this

Genetic Susceptibility to Neurodevelopmental Conditions Is Associated With Neonatal DNA Methylation Patterns in the General Population: an individual participant data meta-analysis

Abstract

Acknowledgements

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

BrainHealth - Decoding life course pathways of mental ageing - Frontier Research Guarantee

Cite this