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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

  • Jim van Os (a1) (a2) (a3), Lotta-Katrin Pries (a2), Philippe Delespaul (a2), Gunter Kenis (a2), Jurjen J. Luykx (a1) (a4), Bochao D. Lin (a1), Alexander L. Richards (a5), Berna Akdede (a6), Tolga Binbay (a6), Vesile Altınyazar (a7), Berna Yalınçetin (a8), Güvem Gümüş-Akay (a9), Burçin Cihan (a10), Haldun Soygür (a11), Halis Ulaş (a11), Eylem Şahin Cankurtaran (a12), Semra Ulusoy Kaymak (a13), Marina M. Mihaljevic (a14) (a15), Sanja Andric Petrovic (a15), Tijana Mirjanic (a16), Miguel Bernardo (a17) (a18) (a19), Bibiana Cabrera (a17) (a19), Julio Bobes (a19) (a20) (a21) (a22), Pilar A. Saiz (a19) (a20) (a21) (a22), María Paz García-Portilla (a19) (a20) (a21) (a22), Julio Sanjuan (a19) (a23), Eduardo J. Aguilar (a19) (a23), José Luis Santos (a19) (a24), Estela Jiménez-López (a19) (a25), Manuel Arrojo (a26), Angel Carracedo (a27), Gonzalo López (a19) (a28), Javier González-Peñas (a19) (a28), Mara Parellada (a19) (a28), Nadja P. Maric (a14) (a15), Cem Atbaşoğlu (a29), Alp Ucok (a30), Köksal Alptekin (a6), Meram Can Saka (a29), Genetic Risk and Outcome Investigators (GROUP), Celso Arango (a19) (a28), Michael O'Donovan (a5), Bart P. F. Rutten (a2) and Sinan Guloksuz (a2) (a31)...

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.

Copyright

Corresponding author

Author for correspondence: Jim van Os, E-mail: j.j.vanos-2@umcutrecht.nl

Footnotes

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*

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.

Footnotes

References

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