Polygenic risk gradient identified across schizophrenia, bipolar disorder

By Marilynn Larkin

NEW YORK (Reuters Health) – A gradient of polygenic liability across schizophrenia and bipolar disorder may explain the clinical heterogeneity within and between the two disorders, researchers suggest.

To investigate the association between schizophrenia-related polygenic liability and psychotic symptoms in bipolar disorder, Dr. Judith Allardyce of Cardiff University, UK, and colleagues conducted a case-control study. They analyzed clinical and genetic data from 4,436 individuals (67% women) diagnosed with bipolar disorder whose mean age at first interview was 46 and compared them with genotypic data for 4,976 people with schizophrenia and 9,012 controls.

Polygenic risk scores (PRS) - representing the full burden of common risk alleles that, individually, would have only a small effect on risk - were calculated and stratified by subtypes of bipolar disorder, lifetime occurrence of psychosis, and lifetime mood-incongruent psychotic features.

As reported in JAMA Psychiatry, online November 22, there was an exposure-response gradient across clinical phenotypes, with the strongest PRS association for schizophrenia (risk ratio, 1.94), followed by schizoaffective bipolar disorder (RR, 1.37), bipolar I disorder (RR, 1.30) and bipolar II disorder (RR, 1.04; nonsignificant).

Within bipolar disorder cases, there was an effect gradient determined by the nature of the psychosis. Prominent mood-incongruent psychotic features had the strongest association (RR, 1.46), followed by mood-congruent psychosis (RR, 1.24) and no psychosis (RR, 1.09).

"For the first time to date, a study shows a polygenic risk gradient across schizophrenia and bipolar disorder, indexed by the occurrence and level of mood-incongruent psychotic symptoms," the authors conclude. They suggest the approach "(moves) us tentatively toward precision medicine in psychiatry."

Three experts commented on the findings in emails to Reuters Health.

Dr. Francis McMahon, Chief of the Human Genetics Branch of the U.S. National Institute of Mental Health and coauthor of an accompanying editorial, said, "This is an interesting study from several perspectives, and a testament to the power of the large sample sizes that can be achieved through team science."

"I think the key clinical point is that genetic risk factors can help shape symptoms in bipolar disorder to some degree, even though a genetic test for diagnosis is still a long way off," he stated. "Researchers will be interested to see how we may begin to use information from large genome-wide association studies to better understand the biological overlap between traditionally distinct psychiatric diagnoses."

Dr. Pablo Gejman, Vice President of Genomic Research at NorthShore University Health System in Chicago, observed, "The work yields further evidence on the relationship between psychosis and common variation in the genome across diagnostic psychiatric categories of mood disorder and schizophrenia."

"The results also provide a glimpse at the possibility of utilizing polygenic risk scores for prediction of risk in a psychiatric clinical context," he added. "However, the risk conferred by currently used psychiatric polygenic scores remains modest."

Dr. Jeffrey Lieberman, Chair of the Department of Psychiatry at Columbia University College of Physicians and Surgeons in New York City, said, "This interesting study provides further evidence for the genetic commonality of schizophrenia, schizoaffective disorder and bipolar disorder conditions which share clinical features including symptoms, illness course and responses to treatment."

"At the same time," he noted, "these findings pose the question of how do common genes have variable expression in different phenotypes?"

"We must continue to follow the genes to elucidate the mysteries of mental illness," Dr. Lieberman concluded.

Neither Dr. Allardyce nor principal author Dr. Valentina Escott-Price responded to requests for comment.

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JAMA Psychiatry 2017.

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