Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study–derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.
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We are grateful to the Lieber and Maltz families for their visionary support that funded the analytic work of this project. We thank all of the participants in the study and their families. We thank Joo Heon Shin for help with the gene expression analyses, and Barbara Gelao, Marina Mancini, Raffaella Romano, Rita Masellis, and Grazia Caforio for help with data acquisition. We also thank Sally Cheung and John Meyer for data management, and Susan Fisher for guidance with placental datasets and review of the manuscript. We thank the Psychiatry Genomics Consortium for providing the statistics for PRS calculation, and Thomas F. McNeil for providing the scale for ELC scoring. We also thank all of the authors of the publicly available placental datasets that have been used in this study. The collection of the ELC and genetic data for the American samples was supported by direct funding from the Intramural Research Program of the NIMH to the Clinical Brain Disorders Branch (D.R.W., PI, protocol 95-M-0150, NCT00001486, annual report number: ZIA MH002942-05), with supplemental analytic support from the Clinical and Translational Neuroscience Branch (K.F.B., PI). G.U. received partial support from P50MH094268. The collection of ELCs and genetic data for the Italian sample has been supported by the NARSAD grant no. 20337 and the “Ricerca Finalizzata” grant no. PE-2011-02347951 (both awarded to A.B.). The GRAS data collection has been supported by funding from the Max Planck Society, the Max Planck Förderstiftung, the DFG (CNMPB), EXTRABRAIN EU-FP7, and the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) (to H.E.).
Supplementary Figures 1–21, Supplementary Tables 2–8, 10–14, and 19–21 and Supplementary Notes
Polygenic risk profile score SNPs
PRS1 and PRS2 genes and their enrichment in placental datasets
Pathway enrichment results
Function enrichment results
Gene Ontology enrichment results
Upstream regulators enrichment results
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Prenatal adverse environment is associated with epigenetic age deceleration at birth and hypomethylation at the hypoxia-responsive EP300 gene
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