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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, Altinyazar, Vesile, Yalinçetin, Berna, Gümüs-Akay, Güvem, Cihan, Burçin, Soygür, 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., 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., Atbasoglu, Cem, Ucok, Alp, Alptekin, Köksal, Saka, Meram Can, Arango, Celso, O'Donovan, Michael, Rutten, Bart P. F. and Guloksuz, Sinan 2020. Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway. Psychological Medicine 10.1017/S0033291720003748
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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.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Cambridge University Press
ISSN: 0033-2917
Date of First Compliant Deposit: 13 November 2020
Date of Acceptance: 22 September 2020
Last Modified: 24 Nov 2020 18:05

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