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

Jim Van Os; Lotta Katrin Pries; Margreet Ten Have; Ron De Graaf; Saskia Van Dorsselaer; Philippe Delespaul; Maarten Bak; Gunter Kenis; Bochao D. Lin; Jurjen J. Luykx; Alexander L. Richards; Berna Akdede; Tolga Binbay; Vesile Altlnyazar; Berna Yallnçetin; GÜvem Gümüş-Akay; Burçin Cihan; Haldun Soygür; Halis Ulaş; Eylem Şahin Cankurtaran; Semra Ulusoy Kaymak; Marina M. Mihaljevic; Sanja Andric Petrovic; Tijana Mirjanic; Miguel Bernardo; Gisela Mezquida; Silvia Amoretti; Julio Bobes; Pilar A. Saiz; María Paz García-Portilla; Julio Sanjuan; Eduardo J. Aguilar; José Luis Santos; Estela Jiménez-López; Manuel Arrojo; Angel Carracedo; Gonzalo López; Javier González-Peñas; Mara Parellada; Nadja P. Maric; Cem Atbaşoǧlu; Alp Ucok; Köksal Alptekin; Meram Can Saka; Celso Arango; Michael O'Donovan; Bart P.F. Rutten; Sinan Guloksuz

doi:10.1017/S0033291720003748

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

Jim Van Os^*, Lotta Katrin Pries, Margreet Ten Have, Ron De Graaf, Saskia Van Dorsselaer, Philippe Delespaul, Maarten Bak, Gunter Kenis, Bochao D. Lin, Jurjen J. Luykx, Alexander L. Richards, Berna Akdede, Tolga Binbay, Vesile Altlnyazar, Berna Yallnçetin, GÜvem Gümüş-Akay, Burçin Cihan, Haldun Soygür, Halis Ulaş, Eylem Şahin CankurtaranSemra Ulusoy Kaymak, Marina M. Mihaljevic, Sanja Andric Petrovic, Tijana Mirjanic, Miguel Bernardo, Gisela Mezquida, Silvia Amoretti, Julio Bobes, Pilar A. Saiz, María Paz García-Portilla, Julio Sanjuan, Eduardo J. Aguilar, José Luis Santos, Estela Jiménez-López, Manuel Arrojo, Angel Carracedo, Gonzalo López, Javier González-Peñas, Mara Parellada, Nadja P. Maric, Cem Atbaşoǧlu, Alp Ucok, Köksal Alptekin, Meram Can Saka, Celso Arango, Michael O'Donovan, Bart P.F. Rutten, Sinan Guloksuz

^*Corresponding author for this work

Psychosis Studies

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Abstract

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.

Original language	English
Pages (from-to)	1910-1922
Number of pages	13
Journal	Psychological Medicine
Volume	52
Issue number	10
DOIs	https://doi.org/10.1017/S0033291720003748
Publication status	Published - 19 Jul 2022

Keywords

Affective pathway
childhood adversity
environment
genetics
psychosis

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10.1017/S0033291720003748

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Van Os, J., Pries, L. K., Ten Have, M., De Graaf, R., Van Dorsselaer, S., Delespaul, P., Bak, M., Kenis, G., Lin, B. D., Luykx, J. J., Richards, A. L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, GÜ., Cihan, B., Soygür, H., Ulaş, H., ... Guloksuz, S. (2022). Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway. Psychological Medicine, 52(10), 1910-1922. https://doi.org/10.1017/S0033291720003748

@article{ba770941bb004323bbbec91b9012e649,

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

abstract = "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. ",

keywords = "Affective pathway, childhood adversity, environment, genetics, psychosis",

author = "{Van Os}, Jim and Pries, {Lotta Katrin} and {Ten Have}, Margreet and {De Graaf}, Ron and {Van Dorsselaer}, Saskia and Philippe Delespaul and Maarten Bak and Gunter Kenis and Lin, {Bochao D.} and Luykx, {Jurjen J.} and Richards, {Alexander L.} and Berna Akdede and Tolga Binbay and Vesile Altlnyazar and Berna Yalln{\c c}etin and G{\"U}vem G{\"u}m{\"u}{\c s}-Akay and Bur{\c c}in Cihan and Haldun Soyg{\"u}r and Halis Ula{\c s} and Cankurtaran, {Eylem {\c S}ahin} and Kaymak, {Semra Ulusoy} and Mihaljevic, {Marina M.} and Petrovic, {Sanja Andric} and Tijana Mirjanic and Miguel Bernardo and Gisela Mezquida and Silvia Amoretti and Julio Bobes and Saiz, {Pilar A.} and Garc{\'i}a-Portilla, {Mar{\'i}a Paz} and Julio Sanjuan and Aguilar, {Eduardo J.} and Santos, {Jos{\'e} Luis} and Estela Jim{\'e}nez-L{\'o}pez and Manuel Arrojo and Angel Carracedo and Gonzalo L{\'o}pez and Javier Gonz{\'a}lez-Pe{\~n}as and Mara Parellada and Maric, {Nadja P.} and Cem Atba{\c s}oǧlu and Alp Ucok and K{\"o}ksal Alptekin and Saka, {Meram Can} and Celso Arango and Michael O'Donovan and Rutten, {Bart P.F.} and Sinan Guloksuz",

note = "Funding Information: 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). Publisher Copyright: Copyright {\textcopyright} The Author(s) 2020. Published by Cambridge University Press.",

year = "2022",

month = jul,

day = "19",

doi = "10.1017/S0033291720003748",

language = "English",

volume = "52",

pages = "1910--1922",

journal = "Psychological Medicine",

issn = "0033-2917",

publisher = "Cambridge University Press",

number = "10",

}

Van Os, J, Pries, LK, Ten Have, M, De Graaf, R, Van Dorsselaer, S, Delespaul, P, Bak, M, Kenis, G, Lin, BD, Luykx, JJ, Richards, AL, Akdede, B, Binbay, T, Altlnyazar, V, Yallnçetin, B, Gümüş-Akay, GÜ, Cihan, B, Soygür, H, Ulaş, H, Cankurtaran, EŞ, Kaymak, SU, Mihaljevic, MM, Petrovic, SA, Mirjanic, T, Bernardo, M, Mezquida, G, Amoretti, S, Bobes, J, Saiz, PA, García-Portilla, MP, Sanjuan, J, Aguilar, EJ, Santos, JL, Jiménez-López, E, Arrojo, M, Carracedo, A, López, G, González-Peñas, J, Parellada, M, Maric, NP, Atbaşoǧlu, C, Ucok, A, Alptekin, K, Saka, MC, Arango, C, O'Donovan, M, Rutten, BPF & Guloksuz, S 2022, '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. https://doi.org/10.1017/S0033291720003748

TY - JOUR

T1 - Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway

AU - Van Os, Jim

AU - Pries, Lotta Katrin

AU - Ten Have, Margreet

AU - De Graaf, Ron

AU - Van Dorsselaer, Saskia

AU - Delespaul, Philippe

AU - Bak, Maarten

AU - Kenis, Gunter

AU - Lin, Bochao D.

AU - Luykx, Jurjen J.

AU - Richards, Alexander L.

AU - Akdede, Berna

AU - Binbay, Tolga

AU - Altlnyazar, Vesile

AU - Yallnçetin, Berna

AU - Gümüş-Akay, GÜvem

AU - Cihan, Burçin

AU - Soygür, Haldun

AU - Ulaş, Halis

AU - Cankurtaran, Eylem Şahin

AU - Kaymak, Semra Ulusoy

AU - Mihaljevic, Marina M.

AU - Petrovic, Sanja Andric

AU - Mirjanic, Tijana

AU - Bernardo, Miguel

AU - Mezquida, Gisela

AU - Amoretti, Silvia

AU - Bobes, Julio

AU - Saiz, Pilar A.

AU - García-Portilla, María Paz

AU - Sanjuan, Julio

AU - Aguilar, Eduardo J.

AU - Santos, José Luis

AU - Jiménez-López, Estela

AU - Arrojo, Manuel

AU - Carracedo, Angel

AU - López, Gonzalo

AU - González-Peñas, Javier

AU - Parellada, Mara

AU - Maric, Nadja P.

AU - Atbaşoǧlu, Cem

AU - Ucok, Alp

AU - Alptekin, Köksal

AU - Saka, Meram Can

AU - Arango, Celso

AU - O'Donovan, Michael

AU - Rutten, Bart P.F.

AU - Guloksuz, Sinan

N1 - Funding Information: 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). Publisher Copyright: Copyright © The Author(s) 2020. Published by Cambridge University Press.

PY - 2022/7/19

Y1 - 2022/7/19

N2 - 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.

AB - 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.

KW - Affective pathway

KW - childhood adversity

KW - environment

KW - genetics

KW - psychosis

UR - http://www.scopus.com/inward/record.url?scp=85135497921&partnerID=8YFLogxK

U2 - 10.1017/S0033291720003748

DO - 10.1017/S0033291720003748

M3 - Article

AN - SCOPUS:85135497921

SN - 0033-2917

VL - 52

SP - 1910

EP - 1922

JO - Psychological Medicine

JF - Psychological Medicine

IS - 10

ER -

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

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