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Genetic Links Between Psychotic Experiences, Neuropsychiatric Diseases Uncovered in Study

NEW YORK – There are shared genetic connections between psychotic experiences and conditions on the psychotic spectrum like schizophrenia, but also with conditions like major depressive disorder and autism spectrum disorder, a new genetic association study has found.

Estimates suggest that at least 5 percent and up to 10 percent of the general population has had at least one psychotic experience, such as hallucinations or delusions, but doesn't have a neuropsychiatric condition.

In a new analysis, researchers from Cardiff University turned to data from the UK Biobank to tease out whether the genetic liability for having a psychotic experience overlaps with that of neuropsychiatric diseases. As they reported in JAMA Psychiatry today, the researchers uncovered four genetic loci associated with psychotic experiences and found genetic associations between those experiences and schizophrenia, major depressive disorder, autism spectrum disorder, and other conditions.

"In the largest GWAS of psychotic experiences from the population-based UK Biobank sample, we found support for a shared genetic liability between psychotic experiences and several psychiatric disorders," Cardiff's James Walters and his colleagues wrote in their paper, "indicating that psychotic experiences are not specifically associated with schizophrenia, but rather with a general risk for mental health disorders."

While there is data on nearly 500,000 individuals in the UK Biobank, only about a third of those individuals filled out a mental health questionnaire. That survey asked participants about whether they had previously experienced any visual or auditory hallucinations or delusions of reference or persecution and how distressing these experiences were to them. After removing any individuals diagnosed with a neuropsychiatric condition, the researchers had a sample of 7,803 individuals who reported experiencing at least one psychotic experience. The 147,461 individuals who reported no such experience served as the control group.

Through a genome-wide association study of any psychotic experience, the researchers identified two variants, an intronic variant in Ankyrin-3 (ANK3) and an intergenic variant rs10994278. ANK3 encodes ankyrin-G, a protein that regulates the assembly of voltage-gated sodium channels and is needed for normal synaptic function. ANK3, the researchers noted, has also been tied to bipolar disorder.

A second GWAS limited to the 2,143 individuals who rated their psychotic experiences to be distressing identified two additional variants, one in an intron of cannabinoid receptor 2 (CNR2) and an intergenic variant rs3849810. CNR2 encodes CB2, one of the two well-known cannabinoid receptors.

A third GWAS of the 3,337 individuals who reported multiple psychotic experiences didn't turn up any additional loci.

A genetic correlation analysis revealed genetic links between psychotic experience and major depressive disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, and schizophrenia. Additionally, through polygenic risk score-based analysis, the researchers further uncovered associations between any psychotic experience and the genetic liability for schizophrenia, major depressive disorder, bipolar disorder, ADHD, and neurodevelopment disorder.

This, the researchers said, indicated that psychotic experiences are not specific to schizophrenia, but may reflect a general risk for mental health disorders.

They also particularly found an enrichment of these polygenic risk scores in distressing psychotic experiences and in delusions of persecution.

"This finding speaks to the possibility that some of the genetic contributions identified by the authors may not be associated with the psychotic experiences themselves but rather with susceptibility to distress or dysfunction caused by these and other psychiatric symptoms," writes Albert Powers, an assistant professor of psychiatry at Yale University, in a related editorial that also appears in JAMA Psychiatry.