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

Genetic susceptibility to neurodevelopmental conditions associates 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.

ABSTRACT

OBJECTIVE: 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. Yet, it is unclear whether: (i) genetic susceptibility to neurodevelopmental conditions associates with DNAm patterns already at birth; (ii) DNAm patterns are unique or shared across conditions, and (iii) 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 schizophrenia (measured with polygenic scores [PGSs]) and cord blood DNAm in four European population-based cohorts (npooled=5,802; 50.2% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Further, 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, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex, supporting an early-origins perspective on schizophrenia. Functional characterization confirmed strong genetic effects, 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. 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 explained variance for several cognitive and motor outcomes.

CONCLUSIONS: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm in the general population.

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