O4.7. PLACENTAL GENE EXPRESSION, OBSTETRICAL HISTORY AND POLYGENIC RISK FOR SCHIZOPHRENIA

Abstract Background Early life events influence later susceptibility to many adult diseases and may contribute to define the environmental context in which genes enhance risk for complex disorder like schizophrenia. Here we analyze the role of intrauterine and perinatal environment in modulating the association of schizophrenia with genomic risk. Methods We evaluated whether genomic risk for schizophrenia interacts with intrauterine and perinatal complications (Early Life Complications, ELCs) on case-control status, in three independent samples of healthy subjects and patients with schizophrenia from USA (n=501), Italy (n=273) and Germany (n=919). We further analyzed the relationship between genomic risk and ELCs in two samples of only patients with schizophrenia from Germany (n=1019) and Japan (n=172). Genomic risk was measured with polygenic risk profile scores based on GWAS-significant alleles (PRS), while ELCs history was assessed with the McNeil-Sjöström Scale. We tested whether genes overlapping the schizophrenia 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 (PlacPRS genes) drive the interaction between PRS and ELCs, and performed pathway analyses on PlacPRS genes. Results PRS interacts with ELCs on case-control status, in the three independent samples from USA (p= p=0.004), Italy (p=0.018) and Germany (p=0.018); in each sample the variance of schizophrenia explained by PRS is multiplicatively higher in the presence of a history of ELCs compared with the absence of such events. The relationship between genomic risk and ELCs is further replicated in the two independent samples of only cases from Germany (p=0.047) and Japan (p=0.044). The gene-set based on PRS loci interacting with ELCs is highly expressed in multiple placental tissues (p