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- Title
Associations Between Polygenic Risk Score Loading, Psychosis Liability, and Clozapine Use Among Individuals With Schizophrenia.
- Authors
Lin, Bochao D.; Pinzón-Espinosa, Justo; Blouzard, Elodie; van der Horst, Marte Z.; Okhuijsen-Pfeifer, Cynthia; van Eijk, Kristel R.; Guloksuz, Sinan; Peyrot, Wouter J.; Luykx, Jurjen J.
- Abstract
This genetic association study examines polygenic risk scores (PRS) for schizophrenia and groups with different liabilities to schizophrenia spectrum disorders to detect associations between PRS and the likelihood of receiving a prescription of clozapine relative to other antipsychotics. Key Points: Question: Are polygenic risk scores for schizophrenia (PRS-SCZ) associated with a psychosis liability spectrum and a clinician's decision to prescribe clozapine? Findings: In this genetic association study with 2344 participants from 2 cohorts, we found that PRS-SCZ loading was highest among individuals with schizophrenia spectrum disorders taking clozapine, followed by those taking other antipsychotics, their relatives, and unrelated healthy controls. In addition, PRS-SCZ was positively associated with a clozapine prescription relative to other antipsychotics. Meaning: While in this study PRS-SCZ loading increased with greater psychosis liability, in individuals with schizophrenia spectrum disorders and a relatively high PRS-SCZ, clozapine is more likely to be prescribed. Importance: Predictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices. Objective: To examine associations between PRS-SCZ loading and groups with different liabilities to SSD (individuals with SSD taking clozapine, individuals with SSD taking other antipsychotics, their parents and siblings, and unrelated healthy controls) and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics. Design, Setting, and Participants: This genetic association study was a multicenter, observational cohort study with 6 years of follow-up. Included were individuals diagnosed with SSD who were taking clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Data were collected from 2004 until 2021 and analyzed between October 2021 and September 2022. Exposures: Polygenic risk scores for SCZ. Main Outcomes and Measures: Multinomial logistic regression was used to examine possible differences between groups by computing risk ratios (RRs), ie, ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics. Results: Polygenic risk scores for SCZ were generated for 2344 participants (mean [SD] age, 36.95 years [14.38]; 994 female individuals [42.4%]) who remained after quality control screening (557 individuals with SSD taking clozapine, 350 individuals with SSD taking other antipsychotics during the 6-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RRs were significantly different from 1; RRs were highest for individuals with SSD taking clozapine (RR, 3.24; 95% CI, 2.76-3.81; P = 2.47 × 10−46), followed by individuals with SSD taking other antipsychotics (RR, 2.30; 95% CI, 1.95-2.72; P = 3.77 × 10−22), parents (RR, 1.44; 95% CI, 1.25-1.68; P = 1.76 × 10−6), and siblings (RR, 1.40; 95% CI, 1.21-1.63; P = 8.22 × 10−6). Polygenic risk scores for SCZ were positively associated with clozapine vs other antipsychotic use (OR, 1.41; 95% CI, 1.22-1.63; P = 2.98 × 10−6), suggesting a higher likelihood of clozapine prescriptions among individuals with higher PRS-SCZ. Conclusions and Relevance: In this study, PRS-SCZ loading differed between groups of individuals with SSD, their relatives, and unrelated healthy controls, with patients taking clozapine at the far end of PRS-SCZ loading. Additionally, PRS-SCZ was associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies of the value of using PRS-SCZ to personalize antipsychotic treatment.
- Subjects
DISEASE risk factors; MONOGENIC &; polygenic inheritance (Genetics); PEOPLE with schizophrenia; CLOZAPINE; SCHIZOPHRENIA
- Publication
JAMA Psychiatry, 2023, Vol 80, Issue 2, p181
- ISSN
2168-622X
- Publication type
Article
- DOI
10.1001/jamapsychiatry.2022.4234