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.).

Author information


  1. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

    • Gianluca Ursini
    • , Giovanna Punzi
    • , Qiang Chen
    • , Andrew E. Jaffe
    • , Richard E. Straub
    •  & Daniel R. Weinberger
  2. Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy

    • Gianluca Ursini
    • , Giovanna Punzi
    • , Annamaria Porcelli
    • , Giancarlo Maddalena
    • , Giuseppe Blasi
    •  & Alessandro Bertolino
  3. Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Gianluca Ursini
    •  & Daniel R. Weinberger
  4. Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    • Stefano Marenco
    •  & Karen F. Berman
  5. Human Brain Collection Core, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    • Stefano Marenco
  6. Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA

    • Joshua F. Robinson
    •  & Emily G. Hamilton
  7. Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany

    • Marina Mitjans
    • , Martin Begemann
    • , Jan Seidel
    •  & Hannelore Ehrenreich
  8. Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan

    • Hidenaga Yanamori
    •  & Ryota Hashimoto
  9. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    • Andrew E. Jaffe
  10. Merck Research Laboratories, Merck and Co., Inc., Whitehouse Station, NJ, USA

    • Michael F. Egan
  11. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Carlo Colantuoni
    •  & Daniel R. Weinberger
  12. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Carlo Colantuoni
    •  & Daniel R. Weinberger
  13. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    • Carlo Colantuoni
    •  & Daniel R. Weinberger
  14. Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan

    • Ryota Hashimoto
  15. Department of Psychiatry, Psychotherapy, and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany

    • Dan Rujescu
  16. McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Daniel R. Weinberger


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G.U., G.P., and D.R.W. designed the study and interpreted the results. G.U., G.P., J.F.R., E.G.H., A.E.J., and C.C. carried out statistical analyses. G.U., Q.C., M.M., R.E.S., H.E., and D.R.W. organized and performed genotyping, imputation, and risk profile scoring. G.U., S.M., M.B., J.S., K.F.B., M.F.E., R.E.S., G.B., R.H., D.R., H.E., A.B., and D.R.W. organized and carried out subject recruitment and biological material collection in the discovery sample and in the replication samples, whereas G.U., G.P., S.M., A.P., G.M., M.B., H.Y., R.H., D.R., and H.E. carried out ELC assessment. J.F.R. and E.G.H. contributed to the collection of the placental tissue used in the RNA-sequencing analysis and, together with G.U., G.P., C.C., and D.R.W., interpreted the results of the gene set enrichment analyses in placental samples from complicated pregnancies compared with controls. G.U., G.P., and D.R.W. drafted the manuscript, and all authors contributed to the final version of the paper.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Daniel R. Weinberger.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–21, Supplementary Tables 2–8, 10–14, and 19–21 and Supplementary Notes

  2. Reporting Summary

  3. Supplementary Table 1

    Polygenic risk profile score SNPs

  4. Supplementary Table 9

    PRS1 and PRS2 genes and their enrichment in placental datasets

  5. Supplementary Table 15

    Pathway enrichment results

  6. Supplementary Table 16

    Function enrichment results

  7. Supplementary Table 17

    Gene Ontology enrichment results

  8. Supplementary Table 18

    Upstream regulators enrichment results

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