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Updated: Oct 7, 2025

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Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment

Antonio F Pardiñas1, Sophie E Smart1,2, Isabella R Willcocks1

  • 1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.

JAMA Psychiatry
|January 12, 2022
PubMed
Abstract

Insights

Treatment-resistant schizophrenia (TRS) has a polygenic architecture, with genetic links to intelligence and cognition. This study reveals genetic variants associated with TRS, aiding future research into patient outcomes.

Area of Science:

  • Psychiatry
  • Genetics
  • Neuroscience

Background:

  • Treatment-resistant schizophrenia (TRS) affects 20-30% of patients, presenting a significant clinical challenge.
  • The genetic underpinnings of TRS remain largely unknown due to limited well-characterized cohorts.
  • Understanding TRS genetics is crucial for developing targeted therapeutic strategies.

Purpose of the Study:

  • To investigate the genetic architecture of treatment-resistant schizophrenia (TRS).
  • To reassess existing genetic data from schizophrenia studies for TRS-specific associations.
  • To validate findings in independent clinical samples.

Main Methods:

  • Conducted two genome-wide association studies (GWAS) comparing individuals with TRS (n=10,501) and non-TRS (n=20,325).
  • Analyzed allelic association effect size differences to identify TRS-specific genetic variants.
  • Validated findings using polygenic risk score (PRS) profiling in two independent cohorts (CardiffCOGS and STRATA-G).

Main Results:

  • Treatment resistance in schizophrenia was identified as a polygenic trait with 1-4% heritability.
  • Significant genetic correlations were found between TRS and traits related to intelligence and cognition (correlation, 0.41-0.69).
  • Polygenic risk score analysis indicated a positive association between TRS and clozapine use in both validation cohorts.

Conclusions:

  • Common genetic variants are differentially associated with TRS, potentially masked in previous broad schizophrenia studies.
  • Meta-analytic approaches are validated for studying patient outcomes, including treatment resistance.
  • These findings advance the understanding of TRS genetics and inform future research directions.

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