Disambiguating Maternal versus Fetal Etiological Pathways Linking Perinatal and Neurodevelopmental Outcomes

Associations between adverse perinatal events and neurodevelopmental outcomes are well-documented. Determining to what degree these associations reflect genetic versus environmental pathways is complicated by the ∼50% overlap across maternal and fetal genotypes and by indirect effects of the maternal genotype on the prenatal environment.

Genome-wide association study (GWAS) summary statistics for the effect of the fetal and maternal genome on three perinatal traits-birth weight, placental weight, and gestational duration-were sourced from the Early Growth Genetics Consortium and used in Genomic Structural Equation Modeling (SEM) to partition common variant genetic signal into maternal (i.e., indirect, environmentally mediated) and fetal (i.e., direct) genetic factors. Genetic correlations between these factors and 10 publicly available neurodevelopmental outcomes, reflecting language, motor, and general cognitive measures or neurodevelopmental conditions, were estimated. We evaluated replicability of findings in complementary, epidemiological analyses of ∼790,000 Finnish singleton full-siblings.

Genetic correlations between maternal and fetal factors and neurodevelopmental traits were limited, but included a significant genetic correlation between the effect of the fetal genome on gestational duration and ADHD (r_g = -.16, S.E. = .04). Finnish sibling analyses replicated this finding, demonstrating that shorter gestational duration was associated with increased ADHD risk, even after controlling for shared, unmeasured familial confounds (adjusted HR: 0.93, 95% CI [0.91, 0.95]).

Results demonstrate a shared genetic basis between shorter gestational duration and ADHD that is mediated by the direct effect of fetal genetic variants. These findings are consistent with shared fetal genetic influences underlying gestational duration and ADHD liability, rather than strict mediation via indirect, maternal genetic effects.