Genetic susceptibility to neurodevelopmental conditions associates with neonatal DNA methylation patterns in the general population: an individual participant data meta-analysis

I K Schuurmans; D Smajlagic; V Baltramonaityte; A L K Malmberg; A Neumann; N Creasey; J F Felix; H Tiemeier; J B Pingault; D Czamara; K Raïkkönen; C M Page; R Lyle; A Havdahl; J Lahti; E Walton; M Bekkhus; C A M Cecil

doi:10.1101/2024.07.01.24309384

Genetic susceptibility to neurodevelopmental conditions associates with neonatal DNA methylation patterns in the general population: an individual participant data meta-analysis

medRxiv [Preprint]. 2024 Jul 1:2024.07.01.24309384. doi: 10.1101/2024.07.01.24309384.

Authors

I K Schuurmans^{1

2

3}, D Smajlagic⁴, V Baltramonaityte⁵, A L K Malmberg⁶, A Neumann³, N Creasey^{2

3

7}, J F Felix^{2

8}, H Tiemeier^{3

9}, J B Pingault^{7

10}, D Czamara¹¹, K Raïkkönen^{6

12}, C M Page¹³, R Lyle^{13

14}, A Havdahl^{4

15

16}, J Lahti⁶, E Walton⁵, M Bekkhus⁴, C A M Cecil^{1

3

17}

Affiliations

¹ Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
² The Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
³ Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁴ PROMENTA Research Centre, Department of Psychology, University of Oslo, Oslo, Norway.
⁵ Department of Psychology, University of Bath, Bath, United Kingdom.
⁶ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁷ Department of Clinical, Educational, and Health Psychology, Division of Psychology & Language Sciences, University College London, London, UK.
⁸ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁹ Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰ Social, Genetic & Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹¹ Max-Planck-Institute of Psychiatry, Department Genes and Environment, Munich, Germany.
¹² Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
¹³ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
¹⁴ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
¹⁵ PsychGen Centre for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
¹⁶ Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
¹⁷ Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.

Abstract

Background: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes.

Methods: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (n _pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years.

Outcomes: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10^-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS.

Interpretation: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia.

Funding: HorizonEurope; European Research Council.

Keywords: ALSPAC; DNA methylation; Epigenetics; Generation R Study; Genetic susceptibility; MoBa; Neurodevelopmental conditions; PREDO; Population-based.

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Abstract

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