RT Journal Article
T1 Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.
A1 Pardiñas, Antonio F
A1 Smart, Sophie E
A1 Willcocks, Isabella R
A1 Holmans, Peter A
A1 Dennison, Charlotte A
A1 Lynham, Amy J
A1 Legge, Sophie E
A1 Baune, Bernhard T
A1 Bigdeli, Tim B
A1 Cairns, Murray J
A1 Corvin, Aiden
A1 Fanous, Ayman H
A1 Frank, Josef
A1 Kelly, Brian
A1 McQuillin, Andrew
A1 Melle, Ingrid
A1 Mortensen, Preben B
A1 Mowry, Bryan J
A1 Pato, Carlos N
A1 Periyasamy, Sathish
A1 Rietschel, Marcella
A1 Rujescu, Dan
A1 Simonsen, Carmen
A1 St Clair, David
A1 Tooney, Paul
A1 Wu, Jing Qin
A1 Andreassen, Ole A
A1 Kowalec, Kaarina
A1 Sullivan, Patrick F
A1 Murray, Robin M
A1 Owen, Michael J
A1 MacCabe, James H
A1 O'Donovan, Michael C
A1 Walters, James T R
A1 Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC), 
A1 Ajnakina, Olesya
A1 Alameda, Luis
A1 Barnes, Thomas R E
A1 Berardi, Domenico
A1 Bonora, Elena
A1 Camporesi, Sara
A1 Cleusix, Martine
A1 Conus, Philippe
A1 Crespo-Facorro, Benedicto
A1 D'Andrea, Giuseppe
A1 Demjaha, Arsime
A1 Do, Kim Q
A1 Doody, Gillian A
A1 Eap, Chin B
A1 Ferchiou, Aziz
A1 Di Forti, Marta
A1 Guidi, Lorenzo
A1 Homman, Lina
A1 Jenni, Raoul
A1 Joyce, Eileen M
A1 Kassoumeri, Laura
A1 Khadimallah, Inès
A1 Lastrina, Ornella
A1 Muratori, Roberto
A1 Noyan, Handan
A1 O'Neill, Francis A
A1 Pignon, Baptiste
A1 Restellini, Romeo
A1 Richard, Jean-Romain
A1 Schürhoff, Franck
A1 Španiel, Filip
A1 Szöke, Andrei
A1 Tarricone, Ilaria
A1 Tortelli, Andrea
A1 Üçok, Alp
A1 Vázquez-Bourgon, Javier
AB 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. To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. 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]). 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. 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). 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.
YR 2022
FD 2022
LK http://hdl.handle.net/10668/22272
UL http://hdl.handle.net/10668/22272
LA en
DS RISalud
RD Apr 18, 2025