115.1 Placental Gene Expression Mediates the Interaction Between Obstetrical History and Genetic Risk for Schizophrenia

Abstract

Abstract Background: Early life events influence susceptibility to adult diseases and, as such, represent an environmental context in which genes enhance risk for complex disorders. Here we analyze the role of the intrauterine and perinatal environment in modulating genomic risk for schizophrenia, a neurodevelopmental disorder often associated with obstetrical complications. Methods: We evaluated the relationship between genomic risk, intrauterine and perinatal complications (Early Life Complications, ELCs) and schizophrenia in samples from USA, Europe and Eastern Asia (total N = 946). Genomic risk was measured with risk profile scores (RPS) based on GWAS-significant alleles, while ELCs exposure was assessed with the McNeil-Sjostrom Scale. We tested whether genes overlapping the RPS loci interacting with ELCs are enriched in placenta and differentially expressed in placental samples from complicated pregnancies, in 8 independent placental datasets. Finally, we evaluated whether GWAS SNPs marking loci containing genes highly expressed and dynamically modulated in placenta (PlacRPS genes) drive the interaction between RPS and ELCs, and performed pathway analyses on PlacRPS genes. Results: In the USA sample, genetic risk score was associated with schizophrenia only in the context of exposure to ELCs (P = 6.62e-09); similar results were found in the Italian sample (P = .0005), and the relationship between RPS and ELCs was further replicated in the sample of Japanese patients (P < .05). The gene-set based on RPS loci interacting with ELCs is highly expressed in multiple placental tissues (P < .001) and dynamically regulated in placental samples from complicated, in comparison with normal, pregnancies (P < .05). These differences are significantly greater in placentae from male compared with female offspring (P < 10–8). The interaction between RPS and ELCs is largely driven by PlacRPS genes (P = .002); RPS constructed from the remaining loci do not interact with ELCs (NonPlacRPS, P = .60). Pathways associated with NonPlacRPS genes are reminiscent of previous analyses about schizophrenia risk-genes, while PlacRPS genes implicate an orthogonal biology, with roots in the fetal/placental response to hypoxic stress. Conclusion: Our data suggest that the most significant schizophrenia GWAS variants contribute to risk at least partly by converging on a developmental trajectory sensitive to ELCs and altered placental gene expression. The sex-associated effects on placental transcription suggest that the male preponderance of schizophrenia may arise from gene-environment interactions that influence placental biology. These results highlight placental health as a new public health frontier for primary prevention, particularly in high-risk males.