Prioritization of potential causative genes for schizophrenia in placenta

Gianluca Ursini (), Pasquale Di Carlo, Sreya Mukherjee, Qiang Chen, Shizhong Han, Jiyoung Kim, Maya Deyssenroth, Carmen J. Marsit, Jia Chen, Ke Hao, Giovanna Punzi and Daniel R. Weinberger ()
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Gianluca Ursini: Johns Hopkins University Medical Campus
Pasquale Di Carlo: Johns Hopkins University Medical Campus
Sreya Mukherjee: Johns Hopkins University Medical Campus
Qiang Chen: Johns Hopkins University Medical Campus
Shizhong Han: Johns Hopkins University Medical Campus
Jiyoung Kim: Johns Hopkins University Medical Campus
Maya Deyssenroth: Icahn School of Public Health at Mount Sinai
Carmen J. Marsit: Rollins School of Public Health, Emory University
Jia Chen: Icahn School of Public Health at Mount Sinai
Ke Hao: Icahn School of Medicine at Mount Sinai
Giovanna Punzi: Johns Hopkins University Medical Campus
Daniel R. Weinberger: Johns Hopkins University Medical Campus

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes. We performed TWAS in healthy term placentae (N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain (N = 166) and additional placenta TWAS for other disorders/traits. The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness. These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies. Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone.

Date: 2023
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DOI: 10.1038/s41467-023-38140-1

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