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NEMESIS-2 is conducted by the Netherlands Institute of Mental Health and Addiction (Trimbos Institute) in Utrecht. Financial support has been received from the Ministry of Health, Welfare and Sport, with supplementary support from the Netherlands Organization for Health Research and Development (ZonMw). This work was supported by the European Community's Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). These funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Bart PF Rutten was funded by a VIDI award number 91718336 from the Netherlands Scientific Organisation. Drs Guloksuz and van Os are supported by the Ophelia research project, ZonMw grant number: 636340001. Dr O'Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/L010305/1).

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Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway

Publicated to:Psychological Medicine. 52 (10): 1910-1922 - 2022-07-01 52(10), DOI: 10.1017/s0033291720003748

Authors: van Os, Jim; Pries, Lotta-Katrin; ten Have, Margreet; de Graaf, Ron; van Dorsselaer, Saskia; Delespaul, Philippe; Bak, Maarten; Kenis, Gunter; Lin, Bochao D; Luykx, Jurjen J; Richards, Alexander L; Akdede, Berna; Binbay, Tolga; Altinyazar, Vesile; Yalincetin, Berna; Gumus-Akay, Guvem; Cihan, Burcin; Soygur, Haldun; Ulas, Halis; Cankurtaran, Eylem Sahin; Kaymak, Semra Ulusoy; Mihaljevic, Marina M; Petrovic, Sanja Andric; Mirjanic, Tijana; Bernardo, Miguel; Mezquida, Gisela; Amoretti, Silvia; Bobes, Julio; Saiz, Pilar A; Paz Garcia-Portilla, Maria; Sanjuan, Julio; Aguilar, Eduardo J; Luis Santos, Jose; Jimenez-Lopez, Estela; Arrojo, Manuel; Carracedo, Angel; Lopez, Gonzalo; Gonzalez-Penas, Javier; Parellada, Mara; Maric, Nadja P; Atbasoglu, Cem; Ucok, Alp; Alptekin, Koksal; Saka, Meram Can; Arango, Celso; O'Donovan, Michael; Rutten, Bart P F; Guloksuz, Sinan

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Abstract

There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.

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