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Convergence of placenta biology and genetic risk for schizophrenia

Abstract

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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Acknowledgements

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

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.

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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Further reading

Fig. 1: PRS1, ELC history, and schizophrenia in the scz_lie_eur sample (N = 501).
Fig. 2: Liability of schizophrenia explained by genomic risk in the context of ELC history, in the scz_lie_eur sample (N = 501).
Fig. 3: Placental and non-placental genomic risk for schizophrenia.
Fig. 4: Upregulation of schizophrenia risk genes in male compared with female placentae.