Published online by Cambridge University Press: 15 August 2019
First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.
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.
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.
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.
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.