After tracing the origins of schizophrenia to genes expressed in the placenta while in utero, scientists have now zeroed in on the combination of risk factors that could predict which infants are at greatest risk of developing the condition later in life.
The findings reinforce an emerging picture of schizophrenia as a genetic disorder, with a fate determined by complications that can arise during pregnancy.
Researchers from the Lieber Institute for Brain Development at Johns Hopkins University and the University of North Carolina in the US analysed the relationship between key genes and cognitive development in the first few years after birth.
"By identifying the specific genes activated in the placenta that appear to be unique for schizophrenia risk, we have zeroed in on a set of biological processes that could be targeted to improve placental health and reduce schizophrenia risk," says Daniel R. Weinberger, director of the Lieber Institute.
"To date, prevention from early in life has seemed unapproachable if not unimaginable, but these new insights offer possibilities to change the paradigm."
While any possible prevention strategy remains far in the future, the study does inch us closer to understanding how genes determine the development of schizophrenia, and the impact pregnancy has on their expression.
Symptoms of the disorder don't usually appear until early adulthood, revealing itself in a variety of behaviours and symptoms.
In some, schizophrenia is experienced as confusion or disorganised thinking. In more serious cases it can manifest in hallucinations, impeded motor control, and delusions.
What makes the difference in severity, or even how the condition develops in the first place, is still a complete unknown.
Decades of research has resulted in a frustrating mix of clues. Studies on twins suggest for around four out of every five diagnoses, genes play a key role. Yet that still leaves roughly 20 percent of cases without an obvious basis in inheritance.
Population based studies have uncovered correlations between childhood illness, challenges before or shortly after birth, and even a potential role for the season we're born in.
Combining the evidence, it seems the genes we inherit can put us at a disadvantage should the environment our brain is developing within turn nasty at crucial moments.
Weinberger and his team demonstrated in 2018 roughly a third of the genes associated with schizophrenia were expressed by the placenta during complicated pregnancies – especially those with high blood pressure or resulted in a pre-term delivery.
Male infants, it seemed, were for some reason especially at risk of later developing schizophrenia.
Building on this research, the scientists looked again at the genes being expressed in the placenta during early-life complications, seeking correlations with other neurological disorders such as autism or signs of learning challenges.
They found the genomic risk score for schizophrenia was a strong predictor of difficulties in cognitive development in infancy among adults with schizophrenia, as well as the relative size of their brain based on MRI scans.
But there was no indication that these genes predisposed the growing brain to any other conditions.
"Measuring schizophrenia genetic scores in the placenta combined with studying the first two years of cognitive developmental patterns and early life complications could prove to be an important approach to identify those babies with increased risks," says Weinberger.
Having a high risk score isn't a diagnosis of schizophrenia in itself. Even with complications during pregnancy, other genetic environmental factors might compensate, nudging neurological development in other directions.
Brains are complex organs, after all, and we're still teasing apart the multitude of factors that can determine how they're wired.
But knowing there is a risk can help parents develop their own understanding of schizophrenia, and provide their family with the resources they need to help accommodate any possible challenges that come with the disorder.
Perhaps one day there will be options to reduce any negative impacts these 'schizophrenia genes' could have.
"Understanding the trajectories leading to neurodevelopmental disorders is a big challenge, but a necessary one to design strategies aimed at prevention," says Weinberger.
This research was published in PNAS.