PT  - JOURNAL ARTICLE
AU  - Gianluca Ursini
AU  - Giovanna Punzi
AU  - Qiang Chen
AU  - Stefano Marenco
AU  - Joshua F. Robinson
AU  - Annamaria Porcelli
AU  - Emily G. Hamilton
AU  - Marina Mitjans
AU  - Giancarlo Maddalena
AU  - Martin Begemann
AU  - Jan Seidel
AU  - Hidenaga Yanamori
AU  - Andrew E. Jaffe
AU  - Karen F. Berman
AU  - Michael F. Egan
AU  - Richard E. Straub
AU  - Carlo Colantuoni
AU  - Giuseppe Blasi
AU  - Ryota Hashimoto
AU  - Dan Rujescu
AU  - Hannelore Ehrenreich
AU  - Alessandro Bertolino
AU  - Daniel R. Weinberger
TI  - Placental gene expression mediates the interaction between obstetrical history and genetic risk for schizophrenia
AID  - 10.1101/147207
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 147207
4099  - http://biorxiv.org/content/early/2017/06/07/147207.short
4100  - http://biorxiv.org/content/early/2017/06/07/147207.full
AB  - Defining the environmental context in which genes enhance susceptibility can provide insight into the pathogenesis of complex disorders, like schizophrenia. Here we show that the intrauterine and perinatal environment modulates the association of schizophrenia with genomic risk, as measured with polygenic risk scores (PRS) based primarily on GWAS significant variants. Genomic risk interacts with intrauterine and perinatal complications (Early Life Complications, ELCs) in each of three independent samples from USA, Italy and Germany (overall n= 1693, p= 6e-05). In each sample, the liability of schizophrenia explained by PRS is nominally more than five times greater in the presence of a history of ELCs compared with its absence. In each sample, patients with positive ELC histories have higher PRS than patients without ELCs, which is further confirmed in two additional patient samples from Germany and Japan (overall n=2038, p= 1e-04). The gene set based on the schizophrenia loci interacting with ELCs is highly expressed in multiple placental compartments and dynamically regulated in placenta from complicated in comparison with normal pregnancies. The same genes are differentially up-regulated in placentae from male compared with female offspring. The interaction between genomic risk and ELCs is mainly driven by GWAS significant loci enriched for genes highly expressed in the various placenta samples. Molecular pathway analyses based on the genes not driving this interaction reflect previous analyses about schizophrenia risk-genes, while genes highly and differentially expressed in placentae implicate an orthogonal biology involving cellular stress. These results suggest that the most significant genetic variants detected by current schizophrenia GWAS contribute to risk in part by converging on a developmental trajectory sensitive to events affecting placentation, which may underlie the male preponderance of schizophrenia and offer new insights into primary prevention.