Interaction testing and Polygenic risk scoring to estimate the association of common genetic variants with treatment resistance in Schizophrenia
Creators: name: Pardiñas, Antonio F.
name: Smart, Sophie E.
name: Willcocks, Isabella R.
name: Holmans, Peter A.
name: Dennison, Charlotte A.
name: Lynham, Amy J.
name: Legge, Sophie E.
name: Baune, Bernhard T.
name: Bigdeli, Tim B.
name: Cairns, Murray J.
name: Corvin, Aiden
name: Fanous, Ayman H.
name: Frank, Josef
name: Kelly, Brian
name: McQuillin, Andrew
name: Melle, Ingrid
name: Mortensen, Preben B.
name: Mowry, Bryan J.
name: Pato, Carlos N.
name: Periyasamy, Sathish
name: Rietschel, Marcella
name: Rujescu, Dan
name: Simonsen, Carmen
name: Clair, David
name: Tooney, Paul
name: Wu, Jing Qin
name: Andreassen, Ole A.
name: Kowalec, Kaarina
name: Sullivan, Patrick F.
name: Murray, Robin M.
name: Owen, Michael J.
name: MacCabe, James H.
name: O'Donovan, Michael C.
name: Walters, James T. R.
name: Ajnakina, Olesya
name: Alameda, Luis
name: Barnes, Thomas R. E.
name: Berardi, Domenico
name: Bonora, Elena
name: Camporesi, Sara
name: Cleusix, Martine
name: Conus, Philippe
name: Crespo-Facorro, Benedicto
name: D'Andrea, Giuseppe
name: Demjaha, Arsime
name: Do, Kim Q.
name: Doody, Gillian A.
name: Eap, Chin B.
name: Ferchiou, Aziz
name: Forti, Marta
name: Guidi, Lorenzo
name: Homman, Lina
name: Jenni, Raoul
name: Joyce, Eileen M.
name: Kassoumeri, Laura
name: Khadimallah, Inès
name: Lastrina, Ornella
name: Muratori, Roberto
name: Noyan, Handan
name: O'Neill, Francis A.
name: Pignon, Baptiste
name: Restellini, Romeo
name: Richard, Jean-Romain
name: Schürhoff, Franck
name: Španiel, Filip
name: Szöke, Andrei
name: Tarricone, Ilaria
name: Tortelli, Andrea
name: Üçok, Alp
name: Vázquez-Bourgon, Javier
Publisher: name: Universitäts- und Landesbibliothek Sachsen-Anhalt
Year: 2022
Subjects: subject: 610

description: Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.