Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome

Article Article scientifique Article Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome eng 2022-06-29 2022-10 author Alver Maris 0000-0001-6540-1460 930586 author Mancini Valentina 0000-0003-4411-896X 898584 author Läll Kristi author Schneider Maude 594384 author Romano Luciana 134901 author Mägi Reedik author Dermitzakis Emmanouil 542683 author Eliez Stéphan 0000-0002-8269-3028 39336 author Reymond Alexandre collaborator Milani Lili collaborator Nelis Mari 735840 collaborator Esko Tõnu collaborator Metspalu Andres Estonian Biobank Research Team 4191-4200 10.1038/s41380-022-01674-9 35768638 1359-4184 PMC9718680 https://www.nature.com/articles/s41380-022-01674-9 While the recurrent 22q11.2 deletion is one of the strongest genetic risk factors for schizophrenia (SCZ), variability of its associated neuropsychiatric endophenotypes reflects its incomplete penetrance for psychosis development. To assess whether this phenotypic variability is linked to common variants associated with SCZ, we studied the association between SCZ polygenic risk score (PRS) and longitudinally acquired phenotypic information of the Swiss 22q11.2DS cohort ( n = 97, 50% females, mean age 17.7 yr, mean visit interval 3.8 yr). The SCZ PRS with the best predictive performance was ascertained in the Estonian Biobank ( n = 201,146) with LDpred. The infinitesimal SCZ PRS model showed the strongest capacity in discriminating SCZ cases from controls with one SD difference in SCZ PRS corresponding to an odds ratio (OR) of 1.73 (95% CI 1.57-1.90, P = 1.47 × 10 <sup>−29</sup> ). In 22q11.2 patients, random-effects ordinal regression modelling using longitudinal data showed SCZ PRS to have the strongest effect on social anhedonia (OR = 2.09, P = 0.0002), and occupational functioning (OR = 1.82, P = 0.0003) within the negative symptoms course, and dysphoric mood (OR = 2.00, P = 0.002) and stress intolerance (OR = 1.76, P = 0.0002) within the general symptoms course. Genetic liability for SCZ was additionally associated with full scale cognitive decline (β =-0.25, P = 0.02) and with longitudinal volumetric reduction of the right and left hippocampi (β =-0.28, P = 0.005; β = -0.23, P = 0.02, respectively). Our results indicate that the polygenic contribution to SCZ acts upon the threshold-lowering first hit (i.e., the deletion). It modifies the endophenotypes of 22q11.2DS and augments the derailment of developmental trajectories of negative and general symptoms, cognition, and hippocampal volume. Genetics Neuroscience Schizophrenia Predictive marke Dewey 616.89 Dewey 150 Dewey 576.5 Swiss National Science Foundation NCCR SYNAPSY: The synaptic bases of mental diseases (phase II) 158776 CH Programmes Swiss National Science Foundation NCCR 'SYNAPSY - The synaptic bases of mental diseases' (phase III) 185897 CH Programmes Swiss National Science Foundation The Swiss 22q11DS longitudinal cohort: understanding psychosis proneness through negative symptoms 179404 CH Projects Swiss National Science Foundation Assessing the impact of copy number variants (second chapter) 182632 CH Projects European Union through the European Regional Development Fund 2014-2020.4.01.15-00 Estonian Research Council ETAg grant PUTJD901 European Commission International consortium for integrative genomics prediction 101016775 INTERVENE EU H2020 60 Département de psychiatrie 225 135 Département de médecine génétique et développement 21D 108 Section de psychologie 71 false 421 Laboratoire d'imagerie et de psychopathologie développementale 693 Molecular psychiatry 27 10 f32b2fa6-3915-449b-896b-43b548c3ad90 Article (Published version) Public Article-scientifique-from-crossref.pdf 1537036 application/pdf CC BY-4.0 fb90b6bc-e6a3-4d1b-b552-70d4fd494689 Appendix Public 41380_2022_1674_MOESM1_ESM.pdf 3845852 application/pdf openAccess Faculté de médecine / Section de médecine clinique / Département de psychiatrie Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Faculté de psychologie et des sciences de l'éducation / Section de psychologie

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Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome	Molecular psychiatry			2022	251	276

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