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. 2022 Mar 1;79(3):260-269.
doi: 10.1001/jamapsychiatry.2021.3799.

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Antonio F Pardiñas  1 , Sophie E Smart  1   2 , Isabella R Willcocks  1 , Peter A Holmans  1 , Charlotte A Dennison  1 , Amy J Lynham  1 , Sophie E Legge  1 , Bernhard T Baune  3   4   5 , Tim B Bigdeli  6   7   8 , Murray J Cairns  9   10   11 , Aiden Corvin  12 , Ayman H Fanous  6   7 , Josef Frank  13 , Brian Kelly  14 , Andrew McQuillin  15 , Ingrid Melle  16   17 , Preben B Mortensen  18   19 , Bryan J Mowry  20   21 , Carlos N Pato  22   23   7 , Sathish Periyasamy  20   21 , Marcella Rietschel  13 , Dan Rujescu  24   25 , Carmen Simonsen  16   26 , David St Clair  27 , Paul Tooney  9   11 , Jing Qin Wu  28 , Ole A Andreassen  16   17 , Kaarina Kowalec  29   30 , Patrick F Sullivan  30   31   32 , Robin M Murray  2 , Michael J Owen  1 , James H MacCabe  2 , Michael C O'Donovan  1 , James T R Walters  1 ; Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC); Olesya Ajnakina  33   34 , Luis Alameda  2   35   36   37 , Thomas R E Barnes  38 , Domenico Berardi  39 , Elena Bonora  40 , Sara Camporesi  37   41 , Martine Cleusix  41 , Philippe Conus  37 , Benedicto Crespo-Facorro  35   36 , Giuseppe D'Andrea  39 , Arsime Demjaha  2 , Kim Q Do  41 , Gillian A Doody  42 , Chin B Eap  43   44   45   46 , Aziz Ferchiou  47 , Marta Di Forti  48   49 , Lorenzo Guidi  40 , Lina Homman  50   51 , Raoul Jenni  41 , Eileen M Joyce  52 , Laura Kassoumeri  2 , Inès Khadimallah  41 , Ornella Lastrina  39 , Roberto Muratori  40 , Handan Noyan  53 , Francis A O'Neill  51 , Baptiste Pignon  47   54 , Romeo Restellini  37   41 , Jean-Romain Richard  47 , Franck Schürhoff  47   54 , Filip Španiel  55   56 , Andrei Szöke  47   54 , Ilaria Tarricone  40 , Andrea Tortelli  47   57 , Alp Üçok  58 , Javier Vázquez-Bourgon  59   60   61
Collaborators, Affiliations

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Antonio F Pardiñas et al. JAMA Psychiatry. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Baune has received grants from EraPerMEd as well as personal fees from AstraZeneca, Lundbeck, Pfizer, Takeda Pharmaceuticals, Servier, Bristol Myers Squibb, Otsuka, LivaNova, and Janssen-Cilag. Dr Andreassen has received grants from KG Jebsen Stiftelsen, South East Norway Health Authority, Research Council of Norway, and the European Union Horizon 2020 as well as personal fees from HealthLytix, Lundbeck, and Sunovion. Dr Sullivan has received research funding from Lundbeck as well as personal fees from Pfizer, Neumora, Element Genomics, and Roche; is a shareholder of Neumora; and serves on the advisory committee of Lundbeck. Dr Murray has received grants from Medical Research Council as well as personal fees from Janssen, Merck, Otsuka, Sunovian, and Lundbeck. Drs Owen, O’Donovan, and Walters are investigators on a grant from Takeda Pharmaceuticals paid to Cardiff University; Dr Smart is employed by funds from this grant. Dr MacCabe has received research funding and nonfinancial support from Lundbeck. Dr O’Donovan reported grants from the National Institutes of Health, UK Medical Research Council, Commission of the European Union, and Takeda Pharmaceuticals. Dr Walters has received grants from Medical Research Council, National Institutes of Health, and European Union 7th Framework Programme for Research, and Takeda Pharmaceuticals. Dr Barnes is a member of an advisory board for Gedeon Richter. Dr Camporesi has received grants from the Swiss National Centre Competence in Research. Dr Crespo-Facorro has received personal fees from Adamed, Mylan, Angelini, Janssen, Johnson & Johnson, Lundbeck, and Otsuka Pharmaceuticals. Dr Do has received grants from the Swiss National Science Foundation, and Boehringer Ingelheim and has a patent for EP19218841.5 pending. Dr Eap has received grants from the Swiss National Science Foundation and personal fees from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Vifor Pharma, and Zeller. Dr Di Forti has received fees for educational seminars from Lundbeck and Janssen. Dr Szöke has received grants from the European Community’s Seventh Framework Programme. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Manhattan Plot of the Treatment-Resistant Schizophrenia (TRS) vs Non-TRS Interaction Genome-Wide Association Study
Figure 2.
Figure 2.. Polygenic Score Analysis of the Cardiff Cognition in Schizophrenia (CardiffCOGS) Cohort and Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA-G) Cohort Using 3 Different Schizophrenia-Related Polygenic Risk Scores (PRS)
Associations between PRS and treatment resistance in schizophrenia (TRS) were defined as a history of taking clozapine in people with a schizophrenia diagnosis. There were 315 individuals with TRS and 502 individuals with non-TRS in the CardiffCOGS cohort and 71 individuals with TRS and 492 control individuals in the STRATA-G cohort. PGC indicates Psychiatric Genomics Consortium; PRS-CS, polygenic prediction via Bayesian regression and continuous shrinkage priors. Whiskers indicate 95% CIs. aP < .05.
Figure 3.
Figure 3.. Polygenic Profile Derived From Combined Genotype Data From the Cardiff Cognition in Schizophrenia (CardiffCOGS) and Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA-G) Cohorts Using Scores Calculated With Linkage Disequilibrium–Independent (P < 1) Single-Nucleotide Variants
Dots indicate the mean values of the standardized polygenic risk score (PRS; corrected for sex, relevant principal components, and ancestry-informative marker–based ancestry estimates). Whiskers delimit the 95% CIs of the PRS means. PGC indicates Psychiatric Genomics Consortium; TRS, treatment-resistant schizophrenia.
Figure 4.
Figure 4.. Linkage Disequilibrium Score Regression Genetic Correlation Results of LD-HUB Phenotypes With the Treatment-Resistant Schizophrenia Interaction Genome-Wide Association Study
Top, Genetic correlation coefficients shown with standard errors. Bottom, Genetic correlation P values. The dashed line indicates a false discovery rate–corrected significant level of P = .05.
See this image and copyright information in PMC

References

    1. Sullivan PF, Agrawal A, Bulik CM, et al. ; Psychiatric Genomics Consortium . Psychiatric genomics: an update and an agenda. Am J Psychiatry. 2018;175(1):15-27. doi:10.1176/appi.ajp.2017.17030283 - DOI - PMC - PubMed
    1. Paternoster L, Tilling K, Davey Smith G. Genetic epidemiology and mendelian randomization for informing disease therapeutics: conceptual and methodological challenges. PLoS Genet. 2017;13(10):e1006944. doi:10.1371/journal.pgen.1006944 - DOI - PMC - PubMed
    1. Lee JC, Biasci D, Roberts R, et al. ; UK IBD Genetics Consortium . Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn’s disease. Nat Genet. 2017;49(2):262-268. doi:10.1038/ng.3755 - DOI - PMC - PubMed
    1. Rees E, Owen MJ. Translating insights from neuropsychiatric genetics and genomics for precision psychiatry. Genome Med. 2020;12(1):43. doi:10.1186/s13073-020-00734-5 - DOI - PMC - PubMed
    1. Birnbaum R, Weinberger DR. Special article: translational science update. pharmacological implications of emerging schizophrenia genetics: can the bridge from ‘genomics’ to ‘therapeutics’ be defined and traversed? J Clin Psychopharmacol. 2020;40(4):323-329. doi:10.1097/JCP.0000000000001215 - DOI - PubMed

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