Columbia University Scientists Identify Gene Variants Linked to Severe Schizophrenia

New insights into genetic architecture of disease hold promise for improved risk prediction, novel drug design

Columbia University researchers have determined that individuals who suffer from the most severe form of schizophrenia have a significantly higher number of rare mutations than more typical forms of the illness.

Their findings, published on Dec. 13 in the journal PNAS, provide new insight into the genetics of schizophrenia and could pave the way for identifying risk and developing targeted therapeutics for those in need of novel treatments.

“Our results highlight a promising strategy for identifying genetic risk factors for neuropsychiatric disorders that we hope will eventually lead to new and more precise treatments,” said Anthony W. Zoghbi, MD, lead author of the study, who conducted his research at Columbia and is now an assistant professor of psychiatry and behavioral sciences at Baylor College of Medicine.

Schizophrenia, a chronic disorder that disrupts brain functions causing hallucinations, delusions, and other cognitive disturbances, has a high heritability—between 60% and 80%.

Despite considerable progress in identifying genes associated with schizophrenia, scientists have yet to unravel the genetic mechanisms underlying disabling disorder that affects more than 3 million Americans and use that information to develop more effective treatments.

Extreme phenotype strategy

In designing the study the research team employed an “extreme phenotype” strategy that focused on the most severely affected individuals with schizophrenia whose illness had not improved with conventional treatments. Extreme treatment-resistance was defined as illness severity that required an individual’s continuous hospitalization for at least five years in a long-term New York State inpatient facility.

“By enrolling individuals in this important subgroup—who have been underrepresented in genetic studies—we were able to identify the highest burden of rare genetic mutations reported in the schizophrenia literature to date,” Dr. Zohgbi said.

Researchers used whole genome sequencing on 112 individuals with severe, extremely treatment-resistant schizophrenia and 218 individuals with more typical presentations of schizophrenia and compared the results to nearly 5,000 healthy controls.

They found that individuals with the most extreme form of the disease had a significantly higher number of damaging mutations in genes that are relevant to neuropsychiatric disorders compared to both typical forms of schizophrenia and healthy controls.

A total of 48% of individuals with extremely treatment-resistant schizophrenia carried at least one of these rare and damaging mutations, versus roughly 30% of those with typical schizophrenia and 25% of controls.

Predicting Risk, Improving Treatments

Jeffrey A. Lieberman, MD, professor at and chair of the Department of Psychiatry, Columbia University College of Physicians and Surgeons, and a study co-author, said the identification of rare variants associated with severe schizophrenia provides a more complete understanding of the genetic architecture of the disease that could not only help predict who is at risk of developing schizophrenia but also be used to design targeted therapeutics.

“I would hope that these results will provide support for the whole genome sequencing of patients diagnosed with schizophrenia in their first episode of illness so that they are not subject to ineffective treatments and more expeditiously be considered for treatments based on the products of their gene mutation,” Dr. Lieberman said.

Dr. Lieberman added that “this study could not have been done without the vision and cooperation of the New York State Office of Mental Health.”

The study, “high-impact rare genetic variants in severe schizophrenia,” was supported by the Chapman Perelman Foundation and the National Institute of Mental Health.