Examining Rare Variant Risk Factors in Individuals With Schizophrenia

Researchers were better able to detect schizophrenia-associated rare variants when they studied individuals with severe, extremely treatment-resistant schizophrenia (SETRS). Their findings were published in PNAS.

The investigators conducted an extreme phenotype sequencing study of 112 individuals (aged 61.0±9.2 years, 67.9% men) with SETRS, whose illness prompted continuous hospitalization for at least 5 years in a New York State inpatient facility (lifetime stay 24.8±12.6 years). None were diagnosed with intellectual disability. They compared these individuals with 218 individuals with typical schizophrenia who had been seen in outpatient and short-term inpatient settings and 4,929 control individuals with predominantly whole exome sequence.

Individuals with SETRS had higher burden of damaging rare missense variants (rare exome variant ensemble learner (REVEL) > 0.5) compared with control individuals (OR 1.35 P =.011).

Individuals with SETRS had nearly 3 times as many (OR 2.90) damaging missense variants in intolerant genes (pLI > 0.9 OR 1.91) and nearly double (OR 1.91) the rare loss-of-function gene variants compared with control individuals. About half (48.2%) of individuals with SETRS possessed a qualifying missense or loss-of-function variant in intolerant genes. About 30% of individuals with typical schizophrenia had about one-quarter of the control individuals had the variant (OR 2.74).

Missense (OR 3.07) and loss-of-function variants (OR 2.58) in intolerant Mendelian disease genes were more common in individuals with SETRS compared with control individuals.

Qualifying missense genes from the SCHEMA consortium were higher (OR 3.67). Among intolerant schizophrenia-associated genes, missense and loss-of-function gene sets had more qualifying missense (OR 5.01) and loss-of-function variants (OR 5.85).

Patients with SETRS were more likely to carry a damaging missense or loss-of-function variant in an intolerant schizophrenia-associated gene compared with individuals with typical schizophrenia (8.9% vs 2.3% OR 5.48 P =.02) and control individuals (8.9% vs 1.6% OR 5.82 P = 2.6 x 10^-8).

Compared with the individuals with typical schizophrenia, the individuals with SCHEMA were more likely to have at least 1 qualifying missense or loss-of-function variant in intolerant genes (48.2% vs 29.8%). About one-quarter of the control individuals had at least 1 such qualifying missense or loss-of-function variant.

Limitations of the study included limited power and sample size of individuals with SETRS.

“The high rate of identifiable rare variants (many in druggable genes) in severe, extremely treatment-resistant schizophrenia provides an opportunity to functionally characterize these variants in model systems, paving the way for the development of mechanistically targeted therapeutics for patients in dire need of novel treatments,” the researchers said.

“Altogether, these results suggest that extreme phenotype case identification could augment gene discovery efforts in schizophrenia and other psychiatric disorders and offers potential clinical utility.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Zoghbi AW, Dhindsa RS, Golderg TE, et al. High-impact rare genetic variants in severe schizophrenia. PNAS. 118 (51) e2112560118. doi:10.1073/pnas.2112560118