Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.
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Pardiñas Antonio F, Smart Sophie E, Willcocks Isabella R, Holmans Peter A, Dennison Charlotte A, Lynham Amy J, Legge Sophie E, Baune Bernhard T, Bigdeli Tim B, Cairns Murray J, Corvin Aiden, Fanous Ayman H, Frank Josef, Kelly Brian, McQuillin Andrew, Melle Ingrid, Mortensen Preben B, Mowry Bryan J, Pato Carlos N, Periyasamy Sathish, Rietschel Marcella, Rujescu Dan, Simonsen Carmen, St Clair David, Tooney Paul, Wu Jing Qin, Andreassen Ole A, Kowalec Kaarina, Sullivan Patrick F, Murray Robin M, Owen Michael J, MacCabe James H, O'Donovan Michael C, Walters James T R, Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC), Ajnakina Olesya, Alameda Luis, Barnes Thomas R E, Berardi Domenico, Bonora Elena, Camporesi Sara, Cleusix Martine, Conus Philippe, Crespo-Facorro Benedicto, D'Andrea Giuseppe, Demjaha Arsime, Do Kim Q, Doody Gillian A, Eap Chin B, Ferchiou Aziz, Di Forti Marta, Guidi Lorenzo, Homman Lina, Jenni Raoul, Joyce Eileen M, Kassoumeri Laura, Khadimallah Inès, Lastrina Ornella, Muratori Roberto, Noyan Handan, O'Neill Francis A, Pignon Baptiste, Restellini Romeo, Richard Jean-Romain, Schürhoff Franck, Španiel Filip, Szöke Andrei, Tarricone Ilaria, Tortelli Andrea, Üçok Alp, Vázquez-Bourgon Javier
Аннотация
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.