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Psychol Med. 2019 Aug 15:1-14. doi: 10.1017/S003329171900196X. [Epub ahead of print]

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.

Author information

1
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
2
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands.
3
Department of Psychosis Studies, Institute of Psychiatry, King's College London, King's Health Partners, London, UK.
4
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
5
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.
6
Department of Psychiatry, Dokuz Eylul University School of Medicine, Izmir, Turkey.
7
Department of Psychiatry, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey.
8
Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Izmir, Turkey.
9
Ankara University Brain Research Center, Ankara, Turkey.
10
Department of Psychology, Middle East Technical University, Çankaya, Ankara, Turkey.
11
Department of Psychiatry, School of Medicine, Dokuz Eylül University(discharged by decree 701 on July 8, 2018 because of signing "Peace Petition").
12
Güven Çayyolu Healthcare Campus, Ankara, Turkey.
13
Atatürk Research and Training Hospital Psychiatry Clinic, Ankara, Turkey.
14
Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
15
Clinic for Psychiatry CCS, Belgrade, Serbia.
16
Special Hospital for Psychiatric Disorders Kovin, Kovin, Serbia.
17
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
18
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
19
Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain.
20
Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain.
21
Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, Oviedo, Spain.
22
Mental Health Services of Principado de Asturias, SESPA, Oviedo, Spain.
23
Department of Psychiatry, Hospital Clínico Universitario de Valencia, School of Medicine, Universidad de Valencia, INCLIVA, Valencia, Spain.
24
Department of Psychiatry, Hospital Virgen de la Luz, Cuenca, Spain.
25
Universidad de Castilla-La Mancha, Health and Social Research Center, Cuenca, Spain.
26
Department of Psychiatry, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela, SERGAS, Santiago de Compostela, Spain.
27
Fundación Publica Galega de Medicina Xenómica, Hospital Clínico Universitario de Santiago de Compostela, Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
28
Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain.
29
Department of Psychiatry, School of Medicine, Ankara University, Ankara, Turkey.
30
Department of Psychiatry, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey.
31
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.

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:

Cognition; genetics; schizophrenia; schizotypy

PMID:
31414981
DOI:
10.1017/S003329171900196X

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