Maternal health and autism risk: parsing direct and indirect genetic effects using 3-generation family linkage

Despite autism's prominent genetic etiology and early-life origins, parsing genetic effects contributing to the condition into those that operate directly (via allelic transmission to offspring) vs. indirectly (via influencing prenatal environment) remains challenging. We examined this using a novel design leveraging 3-generation family linkage in Danish national registers. The cohort included all children born in Denmark from 1998-2015 and their relatives identified through 3-generation family linkage. The analytic sample comprised full maternal cousin pairs, including parallel (children of mother's sister) and cross cousins (children of mother's brother). Exposures were diagnoses in the index mother previously associated with offspring autism; the outcome was autism diagnosis in cousins of the index child. We used Cox proportional hazards models to estimate associations separately in parallel and cross cousins, followed by comparisons of these hazard ratios to infer mechanisms. Several maternal diagnoses (e.g., postpartum hemorrhage, personality disorders, epilepsy) were associated with autism in both parallel and cross cousins, consistent with shared direct genetic effects. Other conditions (e.g., false labor, recurrent major depressive disorder, other anxiety disorders, systemic connective tissue involvement) showed stronger associations in parallel than cross cousins, supporting additional indirect genetic effects operating through the prenatal environment. Adjustment for the same diagnosis in the cousin's own mother did not substantially change estimates, providing no evidence for an additional role of non-genetic mechanisms associated with the diagnosis. These findings suggest that both direct and indirect genetic effects contribute to observed links between maternal health and offspring autism, highlighting etiologic heterogeneity and highlighting a registry-based family design to separate these pathways without genetic data.