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Replicated evidence that endophenotypic expression of schizophrenia polygenic risk is greater in healthy siblings of patients compared to controls, suggesting gene–environment interaction. The EUGEI study

Published online by Cambridge University Press:  15 August 2019

Jim van Os Open the ORCID record for Jim van Os [Opens in a new window] ,
Lotta-Katrin Pries ,
Philippe Delespaul ,
Gunter Kenis ,
Jurjen J. Luykx ,
Bochao D. Lin ,
Alexander L. Richards ,
Berna Akdede ,
Tolga Binbay  and
Vesile Altınyazar
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Jim van Os*
Affiliation:
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands Department of Psychosis Studies, Institute of Psychiatry, King's College London, King's Health Partners, London, UK
Lotta-Katrin Pries
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands
Philippe Delespaul
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands
Gunter Kenis
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands
Jurjen J. Luykx
Affiliation:
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Bochao D. Lin
Affiliation:
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Alexander L. Richards
Affiliation:
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
Berna Akdede
Affiliation:
Department of Psychiatry, Dokuz Eylul University School of Medicine, Izmir, Turkey
Tolga Binbay
Affiliation:
Department of Psychiatry, Dokuz Eylul University School of Medicine, Izmir, Turkey
Vesile Altınyazar
Affiliation:
Department of Psychiatry, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey
Berna Yalınçetin
Affiliation:
Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Izmir, Turkey
Güvem Gümüş-Akay
Affiliation:
Ankara University Brain Research Center, Ankara, Turkey
Burçin Cihan
Affiliation:
Department of Psychology, Middle East Technical University, Çankaya, Ankara, Turkey
Haldun Soygür
Affiliation:
Department of Psychiatry, School of Medicine, Dokuz Eylül University (discharged by decree 701 on July 8, 2018 because of signing “Peace Petition”)
Halis Ulaş
Affiliation:
Department of Psychiatry, School of Medicine, Dokuz Eylül University (discharged by decree 701 on July 8, 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 Clinic for Psychiatry CCS, Belgrade, Serbia
Sanja Andric Petrovic
Affiliation:
Clinic for Psychiatry CCS, Belgrade, Serbia
Tijana Mirjanic
Affiliation:
Special Hospital for Psychiatric Disorders Kovin, Kovin, 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 (IDIBAPS), Barcelona, Spain Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain
Bibiana Cabrera
Affiliation:
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain
Julio Bobes
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, Oviedo, Spain Mental Health Services of Principado de Asturias, SESPA, Oviedo, Spain
Pilar A. Saiz
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, Oviedo, Spain Mental Health Services of Principado de Asturias, SESPA, Oviedo, Spain
María Paz García-Portilla
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, Oviedo, Spain Mental Health Services of Principado de Asturias, SESPA, Oviedo, Spain
Julio Sanjuan
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Department of Psychiatry, Hospital Clínico Universitario de Valencia, School of Medicine, Universidad de Valencia, INCLIVA, Valencia, Spain
Eduardo J. Aguilar
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Department of Psychiatry, Hospital Clínico Universitario de Valencia, School of Medicine, Universidad de Valencia, INCLIVA, Valencia, Spain
José Luis Santos
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Department of Psychiatry, Hospital Virgen de la Luz, Cuenca, Spain
Estela Jiménez-López
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Universidad de Castilla-La Mancha, Health and Social Research Center, Cuenca, Spain
Manuel Arrojo
Affiliation:
Department of Psychiatry, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela, SERGAS, Santiago de Compostela, Spain
Angel Carracedo
Affiliation:
Fundación Publica Galega de Medicina Xenómica, Hospital Clínico Universitario de Santiago de Compostela, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
Gonzalo López
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Department of Child and Adolescent Psychiatry, 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), Madrid, Spain Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain
Mara Parellada
Affiliation:
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain Department of Child and Adolescent Psychiatry, 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 Clinic for Psychiatry CCS, Belgrade, Serbia
Cem Atbaşoğlu
Affiliation:
Department of Psychiatry, School of Medicine, Ankara University, Ankara, Turkey
Alp Ucok
Affiliation:
Department of Psychiatry, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
Köksal Alptekin
Affiliation:
Department of Psychiatry, Dokuz Eylul University School of Medicine, 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), Madrid, Spain Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain
Michael O'Donovan
Affiliation:
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, 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 Center, Maastricht, the Netherlands
Sinan Guloksuz
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
*
Author for correspondence: Jim van Os, E-mail: [email protected]
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Abstract

Background

First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.

Methods

We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.

Results

In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.

Conclusions

The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.

Keywords

Cognitiongeneticsschizophreniaschizotypy
Type
Original Articles
Information
Psychological Medicine , Volume 50 , Issue 11 , August 2020 , pp. 1884 - 1897
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Copyright
Copyright © Cambridge University Press 2019

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Footnotes

*

Genetic Risk and Outcome of Psychosis (GROUP) Investigators in EUGEI (GROUP-EUGEI) investigators are: Behrooz Z. Alizadeha, Therese van Amelsvoortb, Richard Bruggemana, Wiepke Cahnc,d, Lieuwe de Haane, Bart P. F. Ruttenb, Jurjen J. Luykxc,f, Jim van Osc,b,g and Ruud van Winkelb,h;

aUniversity of Groningen, University Medical Center Groningen, University Center for Psychiatry, Rob Giel Research Center, Groningen, The Netherlands; bMaastricht University Medical Center, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht, The Netherlands; cUniversity Medical Center Utrecht, Department of Psychiatry, UMC Utrecht Brain Centre, Utrecht University, Utrecht, The Netherlands; dAltrecht, General Menthal Health Care, Utrecht, The Netherlands; eAmsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands; fGGNet Mental Health, Apeldoorn, The Netherlands; gKing's College London, King's Health Partners, Department of Psychosis Studies, Institute of Psychiatry, London, UK and hKU Leuven, Department of Neuroscience, Research Group Psychiatry, Leuven, Belgium.

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