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; Christian 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

Biol Psychiatry. 2025 Sep 22:S0006-3223(25)01463-5. doi: 10.1016/j.biopsych.2025.09.005. Online ahead of print.

Authors

Isabel K Schuurmans¹, Dinka Smajlagic², Vilte Baltramonaityte³, Anni L K Malmberg⁴, Alexander Neumann⁵, Nicole Creasey⁶, Janine F Felix⁷, Henning Tiemeier⁸, Jean-Baptiste Pingault⁹, Darina Czamara¹⁰, Katri Raïkkönen¹¹, Christian Magnus Page¹², Robert Lyle¹³, Alexandra Havdahl¹⁴, Jari Lahti⁴, Esther Walton³, Mona Bekkhus², Charlotte A M Cecil¹⁵

Affiliations

¹ Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
² PROMENTA Research Centre, Department of Psychology, University of Oslo, Oslo, Norway.
³ Department of Psychology, University of Bath, Bath, United Kingdom.
⁴ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁵ Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁶ Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Division of Psychology & Language Sciences, Department of Clinical, Educational, and Health Psychology, University College London, London, United Kingdom.
⁷ Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Pediatrics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸ Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Social and Behavioral Sciences, Harvard TH Chan School of Public Health, Boston, Massachusetts.
⁹ Division of Psychology & Language Sciences, Department of Clinical, Educational, and Health Psychology, University College London, London, United Kingdom; Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
¹⁰ Department Genes and Environment, Max-Planck-Institute of Psychiatry, Munich, Germany.
¹¹ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
¹² Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
¹³ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
¹⁴ PsychGen Centre for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Oslo, Norway; Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
¹⁵ Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands; Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: c.cecil@erasmusmc.nl.

PMID: 40992585
DOI: 10.1016/j.biopsych.2025.09.005

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.