Researchers have employed an extreme phenotype strategy to focus on the most severely affected individuals with schizophrenia and subsequently identified high-impact variants for the disorder.
Schizophrenia is a chronic disorder that disrupts brain functions and causes hallucinations, delusions and other cognitive disturbances. It affects more than 3 million Americans and has a high heritability of between 60% and 80%. Despite considerable progress in identifying genes associated with schizophrenia, scientists have yet to unravel the genetic mechanisms underlying the disorder in order to develop more effective treatments.
Extreme phenotype sequencing is a method whereby only the genomes of the most severe cases of a disease are investigated. This approach has proven promising for detecting high-impact, complex genetic origins of disease. However, extreme phenotype sequencing has yet to be applied to studies of severe schizophrenia, until now.
Extreme phenotype sequencing of schizophrenia
Recently, researchers at Columbia University employed an extreme phenotype strategy to focus on the most severely affected individuals with schizophrenia whose illness had not improved with conventional treatments. Their findings, published in PNAS, are hoped to provide new insights into the genetics of schizophrenia and pave the way for the development of targeted therapeutics for those in need of novel treatments.
The team sequenced the whole genomes of 112 individuals with severe, extremely treatment-resistant schizophrenia as well as 218 individuals with typical schizophrenia and 4,929 controls. They then 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.
It was found that 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. This was compared to 29.8% of typical schizophrenia individuals and 25.4% of controls.
High-impact variants in schizophrenia
Essentially, the researchers in this study found that selecting individuals with extremely severe forms of schizophrenia led to a significantly improved ability to detect disease-associated rare variants.
Anthony Zoghbi, lead author of the study, said:
“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. 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.”
These findings have implications for the design of future genetic studies in schizophrenia and highlights a strategy to improve gene discovery efforts in other neuropsychiatric disorders. Additionally, this study demonstrates the power of extreme phenotype sequencing in psychiatric genetics.
Jeffrey Lieberman, co-lead author of this study, explained:
“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.”
Image credit: PsyPost
