Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Co-occurring internalizing and externalizing behavioral problems in childhood are associated with greater symptom persistence and increased psychiatric burden than either in isolation, yet their molecular correlates in early development remain poorly characterized. We analyzed behavioral profiles at ages three and five years in the Norwegian Mother, Father and Child Cohort Study (MoBa), using a multi-layer and multi-cohorts design integrating genome-wide association analysis, polygenic score analysis, epigenome-wide association analysis of cord blood DNA methylation, and co-methylation network analysis. Behavioral profiles were based on previously identified latent classes representing internalizing, aggression, and co-occurring problems at each age. Across six genome-wide association analyses, covering these three behavioral profiles at ages three and five, we identified one genome-wide significant locus for co-occurring problems at age five, led by rs73161798 at chromosome 13q12 ( P = 3.26 × 10 − 8 ). SNP-based heritability estimates were modest (h 2 SNP ≈ 0.03–0.07) but became more consistently detectable from age three to five. Polygenic score analyses provided the most consistent molecular signal, with broader associations at age five across psychiatric, cognitive, and neurodevelopmental domains. In contrast, single-site cord-blood DNA methylation associations were sparse, identifying one age-three cytosine-phosphate-guanine site (CpG) associated with co-occurring problems, annotated to TNKS (cg10976481; P = 9.03 × 10 − 8 ), and three age-five CpGs, including one in the TENM4 locus (cg18224993; P = 6.38 × 10 − 8 ). These methylation associations were then examined in two independent cohorts, ALSPAC and GenR. Co-methylation network analysis identified age-five modules associated with co-occurring profiles, with nominal enrichment for pathways related to neurodevelopment, synaptic organization, neuronal signaling, and plasticity. These findings thus suggest that molecular correlates become more consistently detectable as behavioral phenotypes become more stable across early childhood from age three to five.
Source: Research Square
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Government of the United Kingdom, UK Research and Innovation, Trond Mohn stiftelse, European Commission, University of Bristol, ZonMw, Erasmus Universiteit Rotterdam, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Novo Nordisk, Universitetet i Bergen, Universitetet i Oslo, Norges Forskningsråd, South East Regional Health Authority, HORIZON EUROPE Framework Programme, Medical Research Council, Economic and Social Research Council, Norwegian Institute of Public Health
OpenAlex ID: W7223825888