Disclosures: Pardiñas reports no relevant financial disclosures. Please see the study for all other authors’ relevant disclosures.
January 14, 2022
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Patients’ genetic data may explain treatment-resistant schizophrenia

Disclosures: Pardiñas reports no relevant financial disclosures. Please see the study for all other authors’ relevant disclosures.
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Findings of a genome-wide association study suggested a heritable component of treatment-resistant schizophrenia, according to results published in JAMA Psychiatry.

“Precision psychiatry provides a potential pathway to improve psychiatric classification and develop treatments that are better tailored to specific patients. Major advances in determining the role of genetic variation in the risk of developing psychiatric disorders are helping realize this potential, but the relevance of these findings to patient outcomes and response to treatment is unclear,” Antonio F. Pardiñas, PhD, of the MRC Centre for Neuropsychiatric Genetics and Genomics and the division of psychological medicine and clinical neurosciences at Cardiff University in the U.K., and colleagues wrote.

Pardiñas and colleagues sought to examine the genetic underpinnings of treatment-resistant schizophrenia (TRS) through analysis of genetic data pulled from U.K. schizophrenia studies..

In two genome-wide association studies (GWAS), researchers divided case samples into patients with TRS and patients with non-TRS. Between both studies, they determined the differences in effect sizes for allelic associations because these differences represent treatment resistance rather than schizophrenia. Further, they collected genotype data from the CLOZUK and Psychiatric Genomics Consortium schizophrenia studies. Validation for this output occurred using polygenic risk score profiling of a prevalence sample with 817 participants from the Cardiff Cognition in Schizophrenia (CardiffCOGS) and an incidence sample with 563 participants from the Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA-G).

The researchers compared results of the GWAS with complex polygenic traits using a genetic correlation approach; the results were used for polygenic risk score analysis on the independent validation cohorts using an identical definition for TRS. In all, the study incorporated data from 85,490 participants (56.9% men) in the GWAS stage and 1,380 (62.2% men) in the polygenic risk score validation stage.

Results showed that treatment resistance in schizophrenia appeared to be a polygenic trait with detectable heritability between 1% and 4%.Other traits associated with intelligence and cognition showed genetic correlations with this resistance. Polygenic risk score analysis among the CardiffCOGS sample revealed a positive association between TRS and a history of taking clozapine. Researchers noted replication of this association in the STRATA-G incidence sample.

“In this GWAS, TRS had a small but detectable heritability associated with common risk alleles,” Pardiñas and colleagues wrote. “This is despite differences in cohort characteristics and the use of drug prescription data as a proxy for TRS instead of quantitative metrics.”

“Altogether, these results highlight the usefulness of well-controlled clinical phenotype data in psychiatric genetics to explore beyond diagnostic classifications and into treatment outcome and response to aid precision psychiatry,” they added.