LAUSR

Significance Environmental and genetic risk factors, and the early antecedents of schizophrenia, represent pieces of a puzzle still far from completion. We show that, in infants with a history of prenatal complications, a measure of genomic risk for schizophrenia linked with placental gene expression is associated with early neurodevelopmental trajectories of risk, particularly in male individuals. While the majority of individuals on this altered neurodevelopmental path likely “canalize” back toward normal development, some may not be rescued and instead “decanalize” toward illness. Specific strategies of prevention may benefit from understanding the unique placental effects of schizophrenia genomic risk and from defining which factors contribute to decanalize the neurodevelopmental trajectories of individuals with a history of risk factors who develop schizophrenia. Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792–801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia’s PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.