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

Published online by Cambridge University Press:  19 October 2020


Jim van Os
Affiliation:
Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
Lotta-Katrin Pries
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands
Margreet ten Have
Affiliation:
Department of Epidemiology, Netherlands Institute of Mental Health and Addiction, Utrecht, The Netherlands
Ron de Graaf
Affiliation:
Department of Epidemiology, Netherlands Institute of Mental Health and Addiction, Utrecht, The Netherlands
Saskia van Dorsselaer
Affiliation:
Department of Epidemiology, Netherlands Institute of Mental Health and Addiction, Utrecht, The Netherlands
Philippe Delespaul
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands FACT, Mondriaan Mental Health, Maastricht, The Netherlands
Maarten Bak
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands FACT, Mondriaan Mental Health, Maastricht, The Netherlands
Gunter Kenis
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands
Bochao D. Lin
Affiliation:
Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
Jurjen J. Luykx
Affiliation:
Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands GGNet Mental Health, Apeldoorn, The Netherlands
Alexander L. Richards
Affiliation:
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
Berna Akdede
Affiliation:
Department of Psychiatry, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Tolga Binbay
Affiliation:
Department of Psychiatry, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Vesile Altınyazar
Affiliation:
Department of Psychiatry, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey
Berna Yalınçetin
Affiliation:
Department of Neuroscience, Graduate School of Health Sciences, Dokuz Eylul University, Izmir, Turkey
Güvem Gümüş-Akay
Affiliation:
Department of Physiology, School of Medicine, Ankara University, Ankara, Turkey Brain Research Center, Ankara University, Ankara, Turkey
Burçin Cihan
Affiliation:
Department of Psychology, Middle East Technical University, Ankara, Turkey
Haldun Soygür
Affiliation:
Turkish Federation of Schizophrenia Associations, Ankara, Turkey
Halis Ulaş
Affiliation:
Department of Psychiatry, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey (Discharged by statutory decree No:701 at 8 July 2018 because of signing ‘Peace Petition’)
Eylem Şahin Cankurtaran
Affiliation:
Güven Çayyolu Healthcare Campus, Ankara, Turkey
Semra Ulusoy Kaymak
Affiliation:
Atatürk Research and Training Hospital Psychiatry Clinic, Ankara, Turkey
Marina M. Mihaljevic
Affiliation:
Faculty of Medicine, University of Belgrade, Belgrade, Serbia Institute of Mental Health, Belgrade, Serbia
Sanja Andric Petrovic
Affiliation:
Faculty of Medicine, University of Belgrade, Belgrade, Serbia Institute of Mental Health, Belgrade, Serbia
Tijana Mirjanic
Affiliation:
Faculty of Medicine, University of Belgrade, Belgrade, Serbia Institute of Mental Health, Belgrade, Serbia
Miguel Bernardo
Affiliation:
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain
Gisela Mezquida
Affiliation:
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain
Silvia Amoretti
Affiliation:
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain
Julio Bobes
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain Mental Health Services of Principado de Asturias, Oviedo, Spain
Pilar A. Saiz
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain Mental Health Services of Principado de Asturias, Oviedo, Spain
María Paz García-Portilla
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain Mental Health Services of Principado de Asturias, Oviedo, Spain
Julio Sanjuan
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Psychiatry, Hospital Clínico Universitario de Valencia, School of Medicine, Universidad de Valencia, Valencia, Spain
Eduardo J. Aguilar
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Psychiatry, Hospital Clínico Universitario de Valencia, School of Medicine, Universidad de Valencia, Valencia, Spain
José Luis Santos
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Psychiatry, Hospital Virgen de la Luz, Cuenca, Spain
Estela Jiménez-López
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Universidad de Castilla-La Mancha, Health and Social Research Center, Cuenca, Spain
Manuel Arrojo
Affiliation:
Department of Psychiatry, Instituto de Investigación Sanitaria, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
Angel Carracedo
Affiliation:
Grupo de Medicina Genómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidad de Santiago de Compostela, Santiago de Compostela, Spain Fundación Pública Galega de Medicina Xenómica (SERGAS), IDIS, Santiago de Compostela, Spain
Gonzalo López
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain
Javier González-Peñas
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain
Mara Parellada
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain
Nadja P. Maric
Affiliation:
Faculty of Medicine, University of Belgrade, Belgrade, Serbia Institute of Mental Health, Belgrade, Serbia
Cem Atbaşoğlu
Affiliation:
Department of Psychiatry, School of Medicine, Ankara University, Ankara, Turkey
Alp Ucok
Affiliation:
Department of Psychiatry, Faculty of Medicine, Istanbul University, Istanbul, Turkey
Köksal Alptekin
Affiliation:
Department of Psychiatry, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey Department of Neuroscience, Graduate School of Health Sciences, Dokuz Eylul University, Izmir, Turkey
Meram Can Saka
Affiliation:
Department of Psychiatry, School of Medicine, Ankara University, Ankara, Turkey
Celso Arango
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain
Michael O'Donovan
Affiliation:
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
Bart P. F. Rutten
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands
Sinan Guloksuz
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
Corresponding
E-mail address:

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.


Type
Original Articles
Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

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