| Abstract: | 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.Understanding the deviations from normal trajectories of brain development may be crucial for predicting illness and for prevention. Epidemiological studies have consistently identified early antecedents, including complications during pregnancy (1–4) and delays in developmental milestones (5–8). The incidence of many developmental disorders tends to be higher in males (9), and risk is typically highly heritable (10). While rare and moderately penetrant genetic variations account for a minority of cases, genome-wide association studies (GWASs) show that most risk is attributable to common variants across the genome (11, 12). Genomic risk scores (GRSs) from GWASs allow a much greater prediction of liability of the disorder than single common variant genotypes, but GRSs per se are not useful in predicting individual risk (13).We previously identified an environmental context in early life in which genomic risk for schizophrenia may enhance disease susceptibility (14). We found that the liability of schizophrenia explained by genomic risk (that is, schizophrenia GRS, also referred to as polygenic risk score; PRS) was more than five times higher in individuals with a history of obstetrical complications (here, early-life complications; ELCs; i.e., during pregnancy, at labor/delivery, and early in neonatal life) compared with its absence (14). Such interaction was exclusive of the GRSs constructed from the loci with the most significant associations with schizophrenia (GRS1: GWAS P < 5 × 10−8; GRS2: GWAS P < 1 × 10−6). Genes in the GRS1 and GRS2 loci were more highly expressed in placental tissue compared with genes in GWAS loci not interacting with ELCs (GRS3 to 10); they were up-regulated in placentae from complicated pregnancies and strongly correlated within placenta with expression of immune response genes (14), consistent with previous evidence linking placenta, inflammation, and brain development (15, 16).To investigate the role of placenta biology in the interaction between schizophrenia GRSs and ELCs, we derived sets of GRSs based on single-nucleotide polymorphisms (SNPs) marking schizophrenia-GWAS loci containing genes highly expressed in placenta and differentially expressed in placentae from complicated compared with normal pregnancies (PlacGRSs; placental genomic risk scores) and also from the remaining GWAS loci (NonPlacGRSs; nonplacental genomic risk scores). We found that only PlacGRSs interacted with ELCs on schizophrenia-case control status, while NonPlacGRSs did not, implicating genes involved in placenta stress as driving the interaction between genomic risk and ELCs. These interactions were specifically related to placental gene expression, in that they were not detected when calculating GRSs based on SNPs marking loci highly expressed or epigenetically regulated in other tissues, including various adult and fetal tissues/embryonic cells, and fetal brain. Finally, we detected a much stronger enrichment of expression of the schizophrenia-risk genes in placentae from male compared with female offspring, suggesting a role of placenta in the higher incidence of schizophrenia in males (14).We here investigate whether placental genomic risk for schizophrenia as well as several other developmental disorders and traits is linked with early neurodevelopmental outcomes in individuals with a history of ELCs associated with placenta pathophysiology. Abundant evidence shows that ELCs have implications for early developmental trajectories, including brain size, intellectual development, and neuromotor function as well as for schizophrenia later in life (3, 5, 17–19). Based on these prior observations and our earlier findings (14), we hypothesized that schizophrenia PlacGRSs, in contrast to NonPlacGRSs, have a negative effect on early developmental outcomes, especially in males. Further consistent with our earlier findings, we hypothesized that this negative relationship is characteristic of the PlacGRSs constructed from the placental schizophrenia-GWAS loci with the strongest association with the disorder (PlacGRS1: GWAS P < 5 × 10−8; PlacGRS2: GWAS P < 1 × 10−6). We studied the relationship of PlacGRSs and NonPlacGRSs with brain volume in a unique sample of neonates who underwent MRI scanning shortly after birth, and analyzed the relationship with neurocognitive development at 1 and 2 y of age in the same subjects. Finally, we analyzed the relationship of PlacGRSs and NonPlacGRSs with brain volume in a sample of adult controls and patients with schizophrenia. |
