Associations Between Polygenic Risk Score Loading, Psychosis Liability, and Clozapine Use Among Individuals With Schizophrenia

Abstract

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.

Figure 1.. Scaled Distributions of Polygenic Risk Scores for Schizophrenia (PRS-SCZ)

Individuals with schizophrenia spectrum disorders who were taking clozapine had the highest PRS-SCZ, followed by individuals taking other antipsychotics, parents, siblings, and controls. All differences were statistically significant (t test P < .001), except for the parents-siblings comparison (eTable 7 in Supplement 1). PRS-SCZ was z scored in all samples and visualized per group. The mean PRS-SCZ is 0; hence, PRS values for controls are lower than 0. The bar in the middle of the box plot is the median PRS-SCZ for individuals in each group. The box plot rectangle is delimited by the 25th and 75th percentiles. The widths of the violins reflect the data distributions; the dots represent outliers outside the interval (Q1 − 1.5 × IQR; Q3 + 1.5 × IQR, where Q indicates quartile).

Figure 2.. Odds Ratios by Polygenic Risk Profile

Odds ratios (ORs) increased with greater number of schizophrenia risk alleles in each group, with maximums reached in the fifth quintiles for individuals with schizophrenia spectrum disorders who were taking other antipsychotics relative to controls (panel A: OR, 26.41; 95% CI, 13.72-50.84), for clozapine users relative to controls (panel B: OR, 38.21; 95% CI, 18.96-78.11), and for clozapine users relative to users of other antipsychotics (panel C: OR, 2.50; 95% CI, 1.80-3.93). Odds ratios are shown in a log scale on the y-axis by genetic risk score profile; note the change in scale on each y-axis. Polygenic risk scores were divided into quintiles (1 = lowest, 5 = highest), and 4 dummy variables were created to contrast quintiles 2 through 5 to quintile 1 as reference. Odds ratios and 95% CIs were estimated using logistic regression.