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

Pardiñas, A.F.; Smart, S.E.; Willcocks, I.R.; Holmans, P.A.; Dennison, C.A.; Lynham, A.J.; Legge, S.E.; Baune, B.T.; Bigdeli, T.B.; Cairns, M.J.; Corvin, A.; Fanous, A.H.; Frank, J.; Kelly, B.; McQuillin, A.; Melle, I.; Mortensen, P.B.; Mowry, B.J.; Pato, C.N.; Periyasamy, S.; Rietschel, M.; Rujescu, D.; Simonsen, C.; St Clair, D.; Tooney, P.; Wu, J.Q.; Andreassen, O.A.; Kowalec, K.; Sullivan, P.F.; Murray, R.M.; Owen, M.J.; MacCabe, J.H.; O'Donovan, M.C.; Walters, JTR; Ajnakina, O.; Alameda, L.; Barnes, TRE; Berardi, D.; Bonora, E.; Camporesi, S.; Cleusix, M.; Conus, P.; Crespo-Facorro, B.; D'Andrea, G.; Demjaha, A.; Do, K.Q.; Doody, G.A.; Eap, C.B.; Ferchiou, A.; Di Forti, M.; Guidi, L.; Homman, L.; Jenni, R.; Joyce, E.M.; Kassoumeri, L.; Khadimallah, I.; Lastrina, O.; Muratori, R.; Noyan, H.; O'Neill, F.A.; Pignon, B.; Restellini, R.; Richard, J.R.; Schürhoff, F.; Španiel, F.; Szöke, A.; Tarricone, I.; Tortelli, A.; Üçok, A.; Vázquez-Bourgon, J.

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.

Détails

Télécharger: jamapsychiatry_pardias_2022_oi_210077_1640287782.06347.pdf (1072.86 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0

ID Serval

serval:BIB_A9662B16E7C0

Type

Article: article d'un périodique ou d'un magazine.

Collection

Publications

Institution

UNIL/CHUV

Titre

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

Périodique

JAMA psychiatry

Auteur⸱e⸱s

Pardiñas A.F., Smart S.E., Willcocks I.R., Holmans P.A., Dennison C.A., Lynham A.J., Legge S.E., Baune B.T., Bigdeli T.B., Cairns M.J., Corvin A., Fanous A.H., Frank J., Kelly B., McQuillin A., Melle I., Mortensen P.B., Mowry B.J., Pato C.N., Periyasamy S., Rietschel M., Rujescu D., Simonsen C., St Clair D., Tooney P., Wu J.Q., Andreassen O.A., Kowalec K., Sullivan P.F., Murray R.M., Owen M.J., MacCabe J.H., O'Donovan M.C., Walters JTR, Ajnakina O., Alameda L., Barnes TRE, Berardi D., Bonora E., Camporesi S., Cleusix M., Conus P., Crespo-Facorro B., D'Andrea G., Demjaha A., Do K.Q., Doody G.A., Eap C.B., Ferchiou A., Di Forti M., Guidi L., Homman L., Jenni R., Joyce E.M., Kassoumeri L., Khadimallah I., Lastrina O., Muratori R., Noyan H., O'Neill F.A., Pignon B., Restellini R., Richard J.R., Schürhoff F., Španiel F., Szöke A., Tarricone I., Tortelli A., Üçok A., Vázquez-Bourgon J.

Collaborateur⸱rice⸱s

Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC)

Contributeur⸱rice⸱s

Ripke S., Neale B.M., Farh K.H., Lee P., Bulik-Sullivan B., Collier D.A., Huang H., Pers T.H., Agartz I., Agerbo E., Albus M., Alexander M., Amin F., Bacanu S.A., Begemann M., Belliveau R.A., Bene J., Bergen S.E., Bevilacqua E., Black D.W., Bruggeman R., Buccola N.G., Buckner R.L., Byerley W., Cahn W., Cai G., Campion D., Cantor R.M., Carr V.J., Carrera N., Catts S.V., Chambert K.D., Chan RCK, Chen RYL, Chen EYH, Cheng W., Cheung EFC, Chong S.A., Cloninger C.R., Cohen D., Cohen N., Cormican P., Craddock N., Crowley J.J., Curtis D., Davidson M., Davis K.L., Degenhardt F., Favero J.D., DeLisi L.E., Demontis D., Dikeos D., Dinan T., Djurovic S., Donohoe G., Drapeau E., Duan J., Dudbridge F., Durmishi N., Eichhammer P., Eriksson J., Escott-Price V., Essioux L., Farrell M.S., Franke L., Freedman R., Freimer N.B., Friedl M., Friedman J.I., Fromer M., Genovese G., Georgieva L., Gershon E.S., Giegling I., Giusti-Rodríguez P., Godard S., Goldstein J.I., Golimbet V., Gopal S., Gratten J., Haan L., Hammer C., Hamshere M.L., Hansen M., Hansen T., Haroutunian V., Hartmann A.M., Henskens F.A., Herms S., Hirschhorn J.N., Hoffmann P., Hofman A., Hollegaard M.V., Hougaard D.M., Ikeda M., Joa I., Julià A., Kahn R.S., Kalaydjieva L., Karachanak-Yankova S., Karjalainen J., Kavanagh D., Keller M.C., Kennedy J.L., Khrunin A., Kim Y., Klovins J., Knowles J.A., Konte B., Kucinskas V., Kucinskiene Z.A., Kuzelova-Ptackova H., Kähler A.K., Laurent C., Keong JLC, Lee S.H., Lerer B., Li M., Li T., Liang K.Y., Lieberman J., Limborska S., Loughland C.M., Lubinski J., Lönnqvist J., Macek M., Magnusson PKE, Maher B.S., Maier W., Mallet J., Marsal S., Mattheisen M., Mattingsdal M., McCarley R.W., McDonald C., McIntosh A.M., Meier S., Meijer C.J., Melegh B., Melle I., Mesholam-Gately R.I., Metspalu A., Michie P.T., Milani L., Milanova V., Mokrab Y., Morris D.W., Mors O., Murphy K.C., Myin-Germeys I., Müller-Myhsok B., Nelis M., Nenadic I., Nertney D.A., Nestadt G., Nicodemus K.K., Nikitina-Zake L., Nisenbaum L., Nordin A., O'Callaghan E., O'Dushlaine C., O'Neill F.A., Oh S.Y., Olincy A., Olsen L., Os J.V., Pantelis C., Papadimitriou G.N., Papiol S., Parkhomenko E., Pato M.T., Paunio T., Pejovic-Milovancevic M., Perkins D.O., Pietiläinen O., Pimm J., Pocklington A.J., Powell J., Price A., Pulver A.E., Purcell S.M., Quested D., Rasmussen H.B., Reichenberg A., Reimers M.A., Richards A.L., Roffman J.L., Roussos P., Ruderfer D.M., Salomaa V., Sanders A.R., Schall U., Schubert C.R., Schulze T.G., Schwab S.G., Scolnick E.M., Scott R.J., Seidman L.J., Shi J., Sigurdsson E., Silagadze T., Silverman J.M., Sim K., Slominsky P., Smoller J.W., So H.C., Spencer CCA, Stahl E.A., Stefansson H., Steinberg S., Stogmann E., Straub R.E., Strengman E., Strohmaier J., Stroup T.S., Subramaniam M., Suvisaari J., Svrakic D.M., Szatkiewicz J.P., Söderman E., Thirumalai S., Toncheva D., Tosato S., Veijola J., Waddington J., Walsh D., Wang D., Wang Q., Webb B.T., Weiser M., Wildenauer D.B., Williams N.M., Williams S., Witt S.H., Wolen A.R., Wong EHM, Wormley B.K., Xi H.S., Zai C.C., Zheng X., Zimprich F., Wray N.R., Stefansson K., Visscher P.M., Adolfsson R., Blackwood DHR, Bramon E., Buxbaum J.D., Børglum A.D., Cichon S., Darvasi A., Domenici E., Ehrenreich H., Esko T., Gejman P.V., Gill M., Gurling H., Hultman C.M., Iwata N., Jablensky A.V., Jönsson E.G., Kendler K.S., Kirov G., Knight J., Lencz T., Levinson D.F., Li Q.S., Liu J., Malhotra A.K., McCarroll S.A., Moran J.L., Mortensen P.B., Nöthen M.M., Ophoff R.A., Palotie A., Petryshen T.L., Posthuma D., Riley B.P., Sham P.C., Sklar P., Clair D.S., Weinberger D.R., Wendland J.R., Werge T., Daly M.J., Agbedjro D., Stahl D., Kapur S., Millgate E., Kepinska A., Kravariti E.

ISSN

2168-6238 (Electronic)

ISSN-L

2168-622X

Statut éditorial

Publié

Date de publication

01/03/2022

Peer-reviewed

Oui

Volume

Numéro

Pages

260-269

Langue

anglais

Notes

Publication types: Journal Article
Publication Status: ppublish

Résumé

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.

URN

urn:nbn:ch:serval-BIB_A9662B16E7C00

OAI-PMH

oai:serval.unil.ch:BIB_A9662B16E7C0

DOI

10.1001/jamapsychiatry.2021.3799

Pubmed

35019943

Web of science

000742416600002

Open Access

Oui