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Placenta Influences Gene Variants Linked to Schizophrenia, Affects Disease Risk

NEW YORK (GenomeWeb) – The placenta modulates the genomic risk of developing schizophrenia, according to a new study.

While schizophrenia is highly heritable, the intra-uterine environment has also been reported to play a key role in disease risk. Early-life complications, such as during pregnancy, have also been associated with schizophrenia risk.

In a new study, a Lieber Institute for Brain Development-led team of researchers examined the interaction of polygenic risk scores for schizophrenia, early-life complications, and the intra-uterine environment. As they reported in Nature Medicine yesterday, the researchers found the portion of schizophrenia explained by polygenic risk scores is about five times higher in those with early-life complications than in those without. The researchers further reported that the schizophrenia loci that interact with early-life complications are highly expressed in the placenta.

"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," senior author Daniel Weinberger, CEO of the Lieber Institute, said in a statement.

For a discovery cohort of 501 individuals — 234 patients and 267 controls — of European ancestry from the US, the researchers determined their genomic risk of developing schizophrenia using a polygenic risk score based on the results of a previous genome-wide association study. In this cohort, the polygenic risk score was significantly associated with case-control status.

At the same time, the researchers used an established scale for obstetric complications to gauge the individuals' early-life complications. While the researchers reported that early-life complications didn't differ significantly between cases and controls, they did find that there was a significant interaction between polygenic risk score and severe early-life complications on case-control status.

Weinberger and his colleagues further reported that the liability of schizophrenia explained by the polygenic risk score was highly significant in the context of early-life complications, but not in their absence.

They also tested polygenic risk scores developed from loci that didn't meet the same significance threshold for association with schizophrenia, and found that only the one they'd used, called PRS1, and the next one, called PRS2, made of alleles with strong yet not-as-significant associations interacted with early-life complications on case-control status.

Weinberger and his colleagues largely replicated their findings in four additional cohorts of 273 Italian individuals, 919 German individuals, a second set of 1,020 German individuals, and 172 Japanese individuals.

For the alleles in the two polygenic risk scores, the researchers examined whether the ones that interacted the most with early-life complications were also highly expressed in the placenta. Using RNA sequencing data from placental tissue from the Epigenome Roadmap Project, they found that genes included in PRS1 and PRS2 were more highly expressed there than genes from other, less significant gene sets.

With tissue samples from pregnancies that experienced preeclampsia or intrauterine growth — both classic, severe early-life complications linked on their own to schizophrenia risk — the researchers found that PRS1 and PRS2 genes were enriched among those differentially expressed in placenta. These genes were not among those differentially expressed in tissues from diseases not linked to schizophrenia, such as hepatitis.

This suggested to the researchers that the genes identified through schizophrenia GWAS that interact with early-life complications are expressed in the placenta during early life, and are modulated there during biological stress.

These sets of genes, the researchers noted, are themselves enriched for genes involved in metabolic and cellular stress and hypoxia. These loci, the researchers said, could influence the fetal or placental response to stress and, in that way, influence disease risk.

"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," Weinberger added.