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

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
Altlnyazar, Vesile
Yallnçetin, Berna
Gümüş-Akay, GÜvem
Cihan, Burçin
Soygür, Haldun
Ulaş, Halis
Cankurtaran, Eylem Şahin
Kaymak, Semra Ulusoy
Mihaljevic, Marina M.
Petrovic, Sanja Andric
Mirjanic, Tijana
Bernardo, Miguel
Mezquida, Gisela
Amoretti, Silvia
Bobes, Julio
Saiz, Pilar A.
García-Portilla, María Paz
Sanjuan, Julio
Aguilar, Eduardo J.
Santos, José Luis
Jiménez-López, Estela
Arrojo, Manuel
Carracedo, Angel
López, Gonzalo
González-Peñas, Javier
Parellada, Mara
Maric, Nadja P.
Atbaşoǧlu, Cem
Ucok, Alp
Alptekin, Köksal
Saka, Meram Can
Arango, Celso
O'Donovan, Michael
Rutten, Bart P. F.
Guloksuz, Sinan
Background 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. Methods 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. Results 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). Conclusions 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.
Psychological Medicine


Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study
Guloksuz, Sinan; et. al. (Wiley, 2019-06-01)
Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy-genetic liability measures suggest gene-environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS-SCZ) and environmental exposures ...
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van Os, Jim; et. al. (Cambridge University Press (CUP), 2020-08-01)
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This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation. Methods Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patie...
Citation Formats
J. Van Os et al., “Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway,” Psychological Medicine, vol. 52, no. 10, pp. 1910–1922, 2022, Accessed: 00, 2022. [Online]. Available: https://hdl.handle.net/11511/99666.