Intergenerational Risk Transmission of Neurodevelopmental Disorders: Neural Mediation of Direct and Indirect Genetic Effects
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Neurodevelopmental disorders (NDDs) are highly heritable conditions influenced by a complex interplay of genetic and environmental factors. However, the precise mechanisms linking intergenerational factors to child NDDs remain poorly understood. To address this, we examined the intergenerational transmission of NDD risk in 3,270 families from the Generation R Study. Specifically, we assessed genetic liability for NDDs in relation to offspring brain structure at age 9 and internalizing and externalizing problems at age 14. Using a mother-father-offspring genetic trio design, we differentiated between direct and indirect genetic transmission effects, applying both a transdiagnostic NDD polygenic score (NDV) and disorder-specific polygenic scores for ADHD, ASD, and MDD. We explored cortical surface area, subcortical gray matter volume, and cerebellum volume as potential mediators of these pathways. Our findings indicate that the transdiagnostic genetic component of NDDs is primarily transmitted through direct genetic effects, with a transmission profile most similar to ADHD. The strongest direct genetic effect was observed for externalizing problems (std. β = 0.140, SE = 0.037). Indirect genetic effects were limited to MDD risk, which was associated with offspring internalizing and externalizing behaviors. None of the structural brain markers significantly mediated the direct or indirect genetic transmission pathways, suggesting that global brain measures may have limited value in explaining the intergenerational transmission of NDD risk. These results point to the need for further research into alternative neurobiological markers, as well as environmental determinants, to better understand the pathways linking genetic NDD risk to behavioral outcomes.
