Researchers from the Columbia University Irving Medical Center and the Baylor College of Medicine report that examining genetic mutations in individuals with severe schizophrenia can improve the ability to detect disease-associated rare genetic variants. The team published its study (“High-impact rare genetic variants in severe schizophrenia”) in PNAS.
The research was conducted at the Irving Medical Center and led by Anthony Zoghbi, MD, now assistant professor of molecular and human genetics and psychiatry and behavioral sciences at the Baylor College of Medicine.
Schizophrenia patients have a diverse spectrum of observable symptoms. For this study, the scientists focused on the extreme end of that spectrum—a group of 112 patients with severe, extremely treatment-resistant schizophrenia who have required long-term hospitalization in New York State inpatient facilities.
“The hypothesis is that these patients might have a greater prevalence of disease-causing mutations because they have such a severe form of the illness, and that’s what we ended up seeing,” said Zoghbi, corresponding author of the study and a Beth K. And Stuart C. Yudofsky Scholar at Baylor.
Zoghbi and his team examined mutations across a set of “intolerant” genes, which are infrequently mutated in the healthy, general population. They conducted genetic sequencing and examined the burden of rare, damaging variants impacting gene function in three groups: people with severe schizophrenia, people with typical schizophrenia and a control group of healthy individuals.
More than 48% of individuals with extremely treatment-resistant schizophrenia carried at least one of the rare, damaging variants, versus approximately 30% of those with typical schizophrenia and 25% of the control group. The severe schizophrenia group also had a higher variant burden in genes previously associated with schizophrenia than the group with typical schizophrenia.
“Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes,” write the investigators.
“Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10−5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10−9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10−3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10−7).
“Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10−8).
“These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.”
“We think that this method of study could be a new paradigm for trying to understand how to enrich a genetic signal in a psychiatric disorder by focusing on individuals who are very severely affected by the disease,” said Zoghbi, who also is chief of psychiatric genetics in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor
Identifying rare variant risk factors in individuals with severe schizophrenia could lead to better understanding of prognosis and treatment resistance and to more opportunities for genetic counseling for families impacted by this disease. Zoghbi believes this study also may lay the groundwork for future research on therapeutics to target genetic mutations associated with schizophrenia.
“We hope that this research brings light and attention to these patients who are often left out of cutting-edge research because of the severity of their condition,” he said.