The brain seems an obvious place to begin searching for clues to the origins of complicated neuropsychiatric diseases like schizophrenia, but it may not be the only one. In a recent study in Nature Communications, researchers identified genes expressed in the placenta as potential factors influencing the development of schizophrenia, offering a novel framework for characterizing the disease and studying its origins (1). 

The lifetime risk of schizophrenia is roughly one percent (2). For those affected, it carries a heavy cost on quality of life. Pharmacological treatments are available, but they fail for many individuals with the disease. The lack of effective treatments is largely due to the mysterious origins and mechanisms of schizophrenia (2). 

Recently, genome-wide association studies (GWAS) and epidemiological studies have respectively provided insight into genetic and environmental risk factors for the disease (3,4). However, researchers generally hypothesize that these factors influence schizophrenia development through interactions in the nervous system (5). 

Past studies revealed that complications during pre- and perinatal stages of life are the most common environmental risk factors associated with schizophrenia (6,7). Building off this research, Daniel Weinberger, a psychiatrist and neuroscientist at the Lieber Institute for Brain Development, and his research team found that schizophrenia risk loci were highly expressed in the placenta compared to genes unrelated to schizophrenia, and these risk loci were even more highly expressed in placentae from complicated pregnancies (8). 

“These things get very, very fascinating because it’s such an unexplored area. And [the placenta] is such a fundamental evolutionary aspect of mammalian development,” Weinberger said.

Based on these studies, Weinberger’s team aimed to identify placenta-specific genes associated with schizophrenia risk. To do this, they performed a Transcriptome Wide Association Study (TWAS) on 150 healthy placental samples. They identified more than 130 genes significantly associated with schizophrenia, most of which play critical functions in nutrient sensing and exchange while a fetus is in utero. 

Schizophrenia researchers have pointed to synaptic dysfunction as a potential cause of the disease (9). “What’s really striking is none of these genes are about synaptic plasticity. None of these genes are about synapses,” said Weinberger. “These [genes] are about fundamental properties of placental cells that seek oxygen and invade the uterus.”

Prior research identified differential expression of schizophrenia risk genes in the placenta based on sex, so the research team next performed TWAS in male and female placental samples (8). The researchers discovered that the implicated genes in male versus female placentae involved strikingly different biological processes. While both male and female genes converged on mTOR signaling pathways, male-specific genes involved inflammatory pathways, while female-specific genes involved insulin signaling. “This paper shows that the biology [of schizophrenia] may be different between males and females,” Weinberger said.

These genes are about fundamental properties of placental cells that seek oxygen and invade the uterus.
- Daniel Weinberger, Lieber Institute for Brain Development

To the researchers’ surprise, placental genes implicated in schizophrenia pointed to biological pathways also activated by SARS-CoV-2. Researchers followed up this finding by performing an additional TWAS in cases where the mother was infected with SARS-CoV-2 during pregnancy and compared the results to uninfected pregnancies. The schizophrenia risk genes were upregulated in SARS-CoV-2 positive cases compared to uninfected controls. This may hint at the involvement of the mother’s immune system in modulating offspring schizophrenia risk, which poses public health implications and opens further avenues of research.  

“What you don’t know is if a change in expression in the placenta can cause schizophrenia… So that’s where you have to get animal models” and knock down implicated genes, said Cheryl Rosenfeld, a researcher on the effects of maternal diet on offspring at the University of Missouri who was not involved in the study. “They certainly provide very good candidate genes to start doing those knockdown approaches.” 

The placenta undoubtedly presents a ripe opportunity for understanding the origins of schizophrenia as well as a wide range of developmental disorders. “The placenta offers something that nothing else can do, and that is diagnosing some of these diseases early on by just basically offering potential biomarkers,” said Rosenfeld. “We can’t sample the brain, but we can certainly sample, in one way or another, the placenta.”

References

1. Ursini, G. et al. Prioritization of potential causative genes for schizophrenia in placenta.Nature Communications  14, 2613 (2023).
2. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature  511, 421-427 (2014).
3. Trubetskoy, V. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature  604, 502-508 (2022).
4. Howes, D. et al. Pathways to schizophrenia: the impact of environmental factors. Intl Journal of Neuropsychopharmacology  7, S7-S13 (2004). 
5. Van Os, J., Rutten, B., Poulton, R. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophrenia Bulletin  34, 1066-1082 (2008). 
6. Davies, C. et al. Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis. Lancet Psychiatry  7, 399–410 (2020).
7. Cannon, M., Jones, P. B. & Murray, R. M. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry  159, 1080–1092 (2002).
8. Ursini, G. et al. Convergence of placenta biology and genetic risk for schizophrenia. Nat Med  24, 792–801 (2018).
9. Yin, D.M. Synaptic dysfunction in schizophrenia. Adv Exp Med Biol  970, 493-516 (2012).