Genes expressed by the placenta as a result of pregnancy complications may play a key role in predisposing offspring to develop schizophrenia, according to an international team of scientists headed by researchers at the Lieber Institute for Brain Development (LIBD), which is on the Johns Hopkins Medical Campus. In contrast with prior studies that have focused on how genes implicated in behavioral disorders directly alter prenatal brain development, the new studies, reported in Nature Medicine (“Convergence of Placenta Biology and Genetic Risk for Schizophrenia“), found that many of the genes that impact on the risk for schizophrenia may alter early brain development indirectly by influencing placental health.

The findings suggest that the impact on placental gene expression of complications during pregnancy, labor, delivery, and neonatal life—collectively known as early-life complications (ELC)—may have much wider reaching implications for both maternal and child health and the development of other neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and Tourette syndrome.

“For the first time, we have found an explanation for the connection between early-life complications, genetic risk, and their impact on mental illness, and it all converges on the placenta,” comments research head Daniel R. Weinberger, Ph.D., who is CEO of the LIBD. “The surprising results of this study make the placenta the centerpiece of a new realm of biological investigation related to how genes and the environment interact to alter the trajectory of human brain development.”

Schizophrenia is a complex disorder that is more common in males than in females. Although there is a highly heritable factor associated with the disorder, genetic variation alone has been found to impact only marginally on schizophrenia risk. Genome-wide association studies (GWAS) also indicate that the genetic risk for schizophrenia is associated with many small-effect alleles across the genome.

Nongenetic influences involving the intrauterine environment have also been implicated in explaining some of the nonshared environmental contribution to schizophrenia, the authors write. “An important role for the intrauterine environment in the etiology of schizophrenia is consistent with the disorder’s putative neurodevelopmental origins and is also supported by many epidemiological studies.”  Analyses of collective studies linking schizophrenia with different types of ELC have suggested that ELCs increase the risk of schizophrenia 1.5- to 2.0-fold, which is much higher than the risk attributed to any common genetic variant.

Although existing GWAS aren’t designed to identify complex genetic and environmental heterogeneity in schizophrenia, the researchers hypothesized that genes and environment may interplay in the development of schizophrenia: “The most significant GWAS associations might achieve their statistical status by converging on early developmental mechanisms sensitive to environmental factors that are also relatively common among patients.” To investigate this possibility further, the team conducted a series of studies to look more closely at the role played by the intrauterine environment, and in particular placental gene expression, in modulating the link between genomic risk and schizophrenia.  

The LIBD team studied data on more than 2800 adults, including schizophrenia cases and controls, from a wide range of ethnic backgrounds and in four countries, including the U.S., Europe, and Asia. Comprehensive genetic data and obstetric histories were available for each participant. Findings from the analyses of data from a discovery cohort in the U.S. were subsequently verified in multiple, independent cohorts from other countries.

The analyses indicated that schizophrenia was linked to an interaction between genomic risk for the disorder, measured as polygenic risk scores (PRS) based on significant GWAS alleles, and history of ELCs. More specifically, the results suggested that the top-scoring PRSs are relevant to the etiopathogenesis of schizophrenia—and particularly in the context of ELCs—whereas lower-scoring PRS may be implicated in polygenic mechanisms of schizophrenia that are not directly related to ELCs.

The data further suggested that individuals with high genetic risk and serious ELCs had at least a fivefold greater risk of developing schizophrenia compared with individuals who displayed a high genetic risk, but had no history of ELCs. Interestingly, the results pointed to a central role for the fetal genome, rather than the parental genome. “…the interaction between genomic risk and ELCs is mainly driven by the fetal genome and is relatively independent of gene-interactions related to parental genomes per se,” the researchers write.

While prior studies have highlighted the regulation of schizophrenia risk genes in the fetal brain, the LIBD studies involving highly diverse ethnic cohorts pointed to the “intrauterine context as a likely place where some risk genes for schizophrenia and environmental adversity intersect, with implications not limited to the brain.” Further investigation, including an analysis of RNA sequencing data from placental tissue in the Epigenome Roadmap Project, identified differential expression of schizophrenia risk-associated genes in the placenta from ELC pregnancies, including those with pre-eclampsia and/or intrauterine growth restriction, which are in particularly associated with placental inflammation. “The enrichment of expression in the placenta of genes in schizophrenia GWAS significant loci provides circumstantial evidence that the interaction of these loci with ELCs on risk for schizophrenia arises at least in part because of primary effects in the placenta,” the authors write. “These results indicate that, as predicted, genes mapping to GWAS significant loci that interact with ELCs are more abundantly expressed in placenta than are genes in the other GWAS loci, which do not interact with ELCs.”

The findings that ELCs and genetic factors interact to impact on schizophrenia risk fits in with studies pointing to the placenta as a mediator of stress effects on the developing brain, they suggest. Animal studies have also indicated that the impact of altered placental functioning on neurodevelopment is sex specific, “with males more vulnerable than females to prenatal adversity.” Perhaps not surprisingly, the Lieber Institute team also found that the PRS gene expression was more highly differentially expressed and upregulated in placentae from male, as compared with female, offspring. “These data suggest a sex-biased role for the placenta in expressing genetic risk for schizophrenia,” the researchers suggest.

“These results suggest that the most significant genetic variants detected by current GWASs contribute to risk for schizophrenia at least partly by converging on a developmental trajectory sensitive to intrauterine and perinatal adversity, and linked with abnormal placentation,” the team concludes. “Moreover, the strikingly relative enrichment of expression of schizophrenia risk genes in placentae from male compared with female offspring suggests that gene–environment interactions influencing placental biology may contribute to the higher incidence of schizophrenia in males compared with females.”

They posit that some of the common genes implicated in schizophrenia risk through different biological mechanisms may in fact regulate placental physiology, the risk of ELCs, and so “secondarily the development of the brain,” possibly by interacting with other regulatory mechanisms that act in the fetal brain itself. “Our results also point to the placenta as a crucial mediator of this interaction in relation to schizophrenia in particular, but likely to other neurodevelopmental disorders in general.…” The researchers say their data suggest that further research may point to new strategies for maintaining placental health as a way of preventing schizophrenia, particularly in males with high genetic risk.

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