The continuity of effect of schizophrenia polygenic risk score and patterns of cannabis use on transdiagnostic symptom dimensions at first-episode psychosis: findings from the EU-GEI study
Authors: Quattrone Diego , Reininghaus Ulrich , Richards Alex L. , Tripoli Giada , Ferraro Laura , Quattrone Andrea , Marino Paolo , Rodriguez Victoria , Spinazzola Edoardo , Gayer-Anderson Charlotte , Jongsma Hannah E. , Jones Peter B. , La Cascia Caterina , La Barbera Daniele , Tarricone Ilaria , Bonora Elena , Tosato Sarah , Lasalvia Antonio , Szöke Andrei , Arango Celso , Bernardo Miquel , Bobes Julio , Del Ben Cristina Marta , Menezes Paulo Rossi , Llorca Pierre-Michel , Santos Jose Luis , Sanjuán Julio , Arrojo Manuel , Tortelli Andrea , Velthorst Eva , Berendsen Steven , de Haan Lieuwe , Rutten Bart P. F. , Lynskey Michael T. , Freeman Tom P. , Kirkbride James B. , Sham Pak C. , O’Donovan Michael C. , Cardno Alastair G. , Vassos Evangelos , van Os Jim , Morgan Craig , Murray Robin M. , Lewis Cathryn M. , Di Forti Marta ,   EU-GEI collaborators, Hubbard Kathryn , Beards Stephanie , Stilo Simona A. , Parellada Mara , Fraguas David , Castro Marta Rapado , Andreu-Bernabeu Álvaro , López Gonzalo , Matteis Mario , González Emiliano , Durán-Cutilla Manuel , Díaz-Caneja Covadonga M. , Cuadrado Pedro , Rodríguez Solano José Juan , Carracedo Angel , Costas Javier , Sánchez Emilio , Amoretti Silvia , Lorente-Rovira Esther , Garcia-Portilla Paz , Jiménez-López Estela , Franke Nathalie , van Dam Daniella , Termorshuizen Fabian , Franke Nathalie , van der Ven Elsje , Messchaart Elles , Leboyer Marion , Schürhoff Franck , Jamain Stéphane , Baudin Grégoire , Ferchiou Aziz , Pignon Baptiste , Richard Jean-Romain , Charpeaud Thomas , Tronche Anne-Marie , Frijda Flora , Marrazzo Giovanna , Sideli Lucia , Sartorio Crocettarachele , Seminerio Fabio , Loureiro Camila Marcelino , Shuhama Rosana , Ruggeri Mirella , Bonetto Chiara , Cristofalo Doriana , Berardi Domenico , Seri Marco , D’Andrea Giuseppe 
Published: August 2021

Diagnostic categories do not completely reflect the heterogeneous expression of psychosis. Using data from the EU-GEI study, we evaluated the impact of schizophrenia polygenic risk score (SZ-PRS) and patterns of cannabis use on the transdiagnostic expression of psychosis. We analysed first-episode psychosis patients (FEP) and controls, generating transdiagnostic dimensions of psychotic symptoms and experiences using item response bi-factor modelling. Linear regression was used to test the associations between these dimensions and SZ-PRS, as well as the combined effect of SZ-PRS and cannabis use on the dimensions of positive psychotic symptoms and experiences. We found associations between SZ-PRS and (1) both negative (B = 0.18; 95%CI 0.03–0.33) and positive (B = 0.19; 95%CI 0.03–0.35) symptom dimensions in 617 FEP patients, regardless of their categorical diagnosis; and (2) all the psychotic experience dimensions in 979 controls. We did not observe associations between SZ-PRS and the general and affective dimensions in FEP. Daily and current cannabis use were associated with the positive dimensions in FEP (B = 0.31; 95%CI 0.11–0.52) and in controls (B = 0.26; 95%CI 0.06–0.46), over and above SZ-PRS. We provide evidence that genetic liability to schizophrenia and cannabis use map onto transdiagnostic symptom dimensions, supporting the validity and utility of the dimensional representation of psychosis. In our sample, genetic liability to schizophrenia correlated with more severe psychosis presentation, and cannabis use conferred risk to positive symptomatology beyond the genetic risk. Our findings support the hypothesis that psychotic experiences in the general population have similar genetic substrates as clinical disorders.