Prediction of antipsychotics efficacy based on a polygenic risk score: a real-world cohort study

Marco De Pieri; Marco Ferrari; Giorgio Pistis; Franziska Gamma; Franca Marino; Armin Von Gunten; Philippe Conus; Marco Cosentino; Chin-Bin Eap

doi:10.3389/fphar.2024.1274442

Prediction of antipsychotics efficacy based on a polygenic risk score: a real-world cohort study

Front Pharmacol. 2024 Mar 8:15:1274442. doi: 10.3389/fphar.2024.1274442. eCollection 2024.

Authors

Marco De Pieri^{1

2

3

4}, Marco Ferrari¹, Giorgio Pistis⁵, Franziska Gamma⁶, Franca Marino¹, Armin Von Gunten⁷, Philippe Conus⁵, Marco Cosentino¹, Chin-Bin Eap^{4

8

9

10}

Affiliations

¹ Center for Research in Medical Pharmacology, Varese, Italy.
² PhD Program in Clinical and Experimental Medicine and Medical Humanities, University of Insubria, Varese, Italy.
³ General Psychiatry Service, Hopitaux Universitaires de Genève, Geneva, Switzerland.
⁴ Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland.
⁵ Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland.
⁶ Les Toises Psychiatry and Psychotherapy Center, Lausanne, Switzerland.
⁷ Service of Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland.
⁸ School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
⁹ Center for Research and Innovation in Clinical Pharmaceutical Sciences, University of Lausanne, Lausanne, Switzerland.
¹⁰ Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Lausanne, Switzerland.

Abstract

Background: Response to antipsychotics is subject to a wide interindividual variability, due to genetic and non-genetic factors. Several single nucleotide polymorphisms (SNPs) have been associated with response to antipsychotics in genome-wide association studies (GWAS). Polygenic risk scores (PRS) are a powerful tool to aggregate into a single measure the small effects of multiple risk alleles. Materials and methods: We studied the association between a PRS composed of SNPs associated with response to antipsychotics in GWAS studies (PRS_response) in a real-world sample of patients (N = 460) with different diagnoses (schizophrenia spectrum, bipolar, depressive, neurocognitive, substance use disorders and miscellaneous). Two other PRSs composed of SNPs previously associated with risk of schizophrenia (PRS_{schizophrenia1} and PRS_{schizophrenia2}) were also tested for their association with response to treatment. Results: PRS_response was significantly associated with response to antipsychotics considering the whole cohort (OR = 1.14, CI = 1.03-1.26, p = 0.010), the subgroup of patients with schizophrenia, schizoaffective disorder or bipolar disorder (OR = 1.18, CI = 1.02-1.37, p = 0.022, N = 235), with schizophrenia or schizoaffective disorder (OR = 1.24, CI = 1.04-1.47, p = 0.01, N = 176) and with schizophrenia (OR = 1.27, CI = 1.04-1.55, p = 0.01, N = 149). Sensitivity and specificity were sub-optimal (schizophrenia 62%, 61%; schizophrenia spectrum 56%, 55%; schizophrenia spectrum plus bipolar disorder 60%, 56%; all patients 63%, 58%, respectively). PRS_{schizophrenia1} and PRS_{schizophrenia2} were not significantly associated with response to treatment. Conclusion: PRS_response defined from GWAS studies is significantly associated with response to antipsychotics in a real-world cohort; however, the results of the sensitivity-specificity analysis preclude its use as a predictive tool in clinical practice.

Keywords: GWAS; antipsychotics; personalized medicine; polygenic risk score; response to treatment; single nucleotide polimorphism (SNP).

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work has been funded in part by the Swiss National Research Foundation (CE and PC: 320030-120686, 324730-144064, and 320030-173211; CBE, PC and KJP: 320030-200602).