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. ,   Genetic Risk and Outcome of Psychosis (GROUP) and Clozapine International Consortium (CLOZIN) Investigators, Hasan Alkomiet , Wagner Elias , Pantelis Christos , Everall Ian P. , Ayhan Y. , Babaoğlu M. O. , Bak Maarten , Alink Wouter , Beld E , Bouhuis A , Edlinger M , Erdoğan I .M. , Gutwinski Stefan , Hallikainen Tero , Jeger-land E , Lähteenvuo Markku , de Koning Mariken B. , Morgenroth Carla , Müderrisoğlu A. , Oviedo-Salcedo Tatiana , Schreiter Stefanie , Repo-Tiihonen Eila , Tuppurainen Heli , Veereschild Mike , Veerman Selene R.T. , de Vos M , Cohen Dan , Bogers Jan P.A.M. , Anıl Yağcıoğlu A.E. , Tiihonen Jari , Ripke Stephan , Bousman Chad A. , Van Beek H , Okhuijsen-Pfeifer Cynthia , van der Horst Marte , van Eijk Kristel , Ertuğrul A. , Yoca G. , Görlitz T. , Grootens K.P. , Leucht Stefan , Narang A. , Schneider-Thoma J. , Kahn René S. , Bekema Erwin , Kleymann Phillip , Luykx Jurjen J. , Alizadeh Behrooz Z. , van Amelsvoort Therese , Cahn Wiepke , de Haan Lieuwe , Schirmbeck Frederike , Simons Claudia J.P. , van Os Jim , Rutten Bart , van Winkel Ruud 
Published: December 2022

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.