The genetic links uncovered in this study offer an intriguing, but incomplete look at the risks of psychotic experiences and their complicated intertwinings with other mental disorders, wrote Albert R. Powers III, MD, PhD.

“Penetrance of the genes in question likely depends at least in part on environmental influences, some of which have been studied extensively,” he wrote. “Recently, some have proposed risk stratification by exposome – a composite score of relevant exposures that may increase risk for psychosis and is analogous to the polygenic risk score used [here].

“The combination of environmental and genetic composite scores may lead to improved insight into individualized pathways toward psychotic experiences, highlighting genetic vulnerabilities to specific stressors likely to lead to phenotypic expression. Ultimately, this will require a more sophisticated mapping between phenomenology and biology than currently exists.”

One approach would be to combine deep phenotyping and behavioral analyses in a framework that could link all relevant levels from symptoms to neurophysiology.

“One such framework is predictive processing theory, which is linked closely with the free energy principle and the Bayesian brain hypothesis and attempts to explain perceptual and cognitive phenomena as manifestations of a drive to maintain as accurate an internal model of one’s surroundings as possible by minimizing prediction errors. This relatively simple scheme makes specific – and, importantly, falsifiable – assessments of the mathematical signatures of neurotypical processes and the ways they might break down to produce specific psychiatric symptoms.”

Dr. Powers is an assistant professor at the department of psychiatry at Yale University, New Haven, Conn., and serves as medical director of the PRIME Psychosis Research Clinic at Yale. His comments came in an accompanying editorial (JAMA Psychiatry. 2019 Sep 25. doi: 10.1001/jamapsychiatry.2019.2391 ).