Disentangling direct and indirect genetic pathways to neurodevelopmental risk: brain structure and behavior in a...

Neurodevelopmental disorders (NDDs) are highly heritable, yet the pathways linking parental genetic liability to child outcomes remain poorly understood. Traditional designs cannot easily separate genes transmitted to the child from environmental influences shaped by parental genotypes.

In 3,270 families from the Generation R Study, we applied a mother-father-offspring trio design to disentangle direct genetic effects from indirect parental influences ('genetic nurture'). Polygenic scores (PGSs) included a transdiagnostic neurodevelopmental score (NDV) and disorder-specific scores for ADHD, ASD, and major depressive disorder (MDD). Offspring brain structure (cortical surface area, subcortical gray matter, cerebellar volume) at age 9 and behavioral problems at age 14 were assessed. Structural equation modeling was used to test direct, indirect, and brain-mediated genetic pathways.

Transdiagnostic NDD genetic liability predicted multiple behavioral domains, primarily via direct genetic effects, with similar influence on internalizing and externalizing problems. ADHD PGS effects closely paralleled those of the NDV PGS, whereas ASD and MDD PGSs showed more domain-specific associations. Notably, maternal, but not paternal, MDD genetic liability was indirectly related to behavioral problems across domains, independent of the child's own genetic risk. This maternal pathway was partly reporter-specific but robust for attention problems across both parent and child reports. Global brain measures did not mediate any of the identified genetic pathways.

Intergenerational NDD risk is predominantly driven by direct genetic transmission. However, maternal depression liability exerts additional influence through environmentally mediated pathways. The absence of brain-mediated effects suggests that the gross neural phenotypes examined here do not capture the mechanisms underlying these pathways. Our findings highlight the importance of maternal influences on child NDD outcomes and underscore the need for longitudinal, multimodal research designs that integrate genetic, caregiving, and fine-grained neural phenotyping data to inform targeted prevention and early intervention strategies for at-risk families.