Convergence of placenta biology and genetic risk for schizophrenia

doi:10.1038/s41591-018-0021-y

. 2018 Jun;24(6):792-801.

doi: 10.1038/s41591-018-0021-y. Epub 2018 May 28.

Convergence of placenta biology and genetic risk for schizophrenia

Gianluca Ursini^{1

2

3}, Giovanna Punzi^{1

2}, Qiang Chen¹, Stefano Marenco^{4

5}, Joshua F Robinson⁶, Annamaria Porcelli², Emily G Hamilton⁶, Marina Mitjans⁷, Giancarlo Maddalena², Martin Begemann⁷, Jan Seidel⁷, Hidenaga Yanamori⁸, Andrew E Jaffe^{1

9}, Karen F Berman⁴, Michael F Egan¹⁰, Richard E Straub¹, Carlo Colantuoni^{11

12

13}, Giuseppe Blasi², Ryota Hashimoto^{8

14}, Dan Rujescu¹⁵, Hannelore Ehrenreich⁷, Alessandro Bertolino², Daniel R Weinberger^{16

17

18

19

20

21}

Affiliations

¹ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
² Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
³ Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
⁵ Human Brain Collection Core, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
⁶ Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
⁷ Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
⁸ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁹ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰ Merck Research Laboratories, Merck and Co., Inc., Whitehouse Station, NJ, USA.
¹¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁴ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
¹⁵ Department of Psychiatry, Psychotherapy, and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany.
¹⁶ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. drweinberger@libd.org.
¹⁷ Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
¹⁸ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
¹⁹ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
²⁰ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
²¹ McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.

PMID: 29808008
DOI: 10.1038/s41591-018-0021-y

Convergence of placenta biology and genetic risk for schizophrenia

Gianluca Ursini et al. Nat Med. 2018 Jun.

. 2018 Jun;24(6):792-801.

doi: 10.1038/s41591-018-0021-y. Epub 2018 May 28.

Authors

Affiliations

¹ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
² Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
³ Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
⁵ Human Brain Collection Core, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
⁶ Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
⁷ Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
⁸ Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
⁹ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰ Merck Research Laboratories, Merck and Co., Inc., Whitehouse Station, NJ, USA.
¹¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁴ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
¹⁵ Department of Psychiatry, Psychotherapy, and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany.
¹⁶ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. drweinberger@libd.org.
¹⁷ Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
¹⁸ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
¹⁹ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
²⁰ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.
²¹ McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drweinberger@libd.org.

PMID: 29808008
DOI: 10.1038/s41591-018-0021-y

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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Comment in

Placental gene expression linked to schizophrenia risk.
Wood H. Wood H. Nat Rev Neurol. 2018 Jul;14(7):381. doi: 10.1038/s41582-018-0027-6. Nat Rev Neurol. 2018. PMID: 29875392 No abstract available.
Intersection of schizophrenia genetics and placental complications.
McCarthy MM. McCarthy MM. Nat Med. 2018 Jun;24(6):707-708. doi: 10.1038/s41591-018-0066-y. Nat Med. 2018. PMID: 29875456 No abstract available.

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Convergence of placenta biology and genetic risk for schizophrenia

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