Clustering schizophrenia genes by their temporal expression patterns aids functional interpretation

van der Meer, Dennis, Cheng, Weiqiu, Rokicki, Jaroslav, Fernandez-Cabello, Sara, Shadrin, Alexey, Smeland, Olav B., Ehrhart, Friederike, Gülöksüz, Sinan, Pries, Lotta-Katrin, Lin, Bochao, Rutten, Bart P. F., van Os, Jim, O'Donovan, Michael ORCID: https://orcid.org/0000-0001-7073-2379, Richards, Alexander L., Steen, Nils Eiel, Djurovic, Srdjan, Westlye, Lars T., Andreassen, Ole A., Kaufmann, Tobias, Aguilar, Eduardo J., Akdede, Berna, Alptekin, Köksal, Altinyazar, Vesile, Amoretti, Silvia, Andric-Petrovic, Sanja, Arango, Celso, Arrojo, Manuel, Atbasoglu, Cem, Bernardo, Miguel, Binbay, Tolga, Bobes, Julio, Cankurtaran, Eylem ahin, Carracedo, Angel, Cihan, Burçin, Delespaul, Philippe, García-Portilla, Maria Paz, González-Peñas, Javier, Guloksuz, Sinan, Gümüs-Akay, Güvem, Jiménez-López, Estela, Ulusoy Kaymak, Semra, Kenis, Gunter, Lin, Bochao D., López, Gonzalo, Luykx, Jurjen J., Maric, Nadja P., Mezquida, Gisela, Mihaljevic, Marina M., Mirjanic, Tijana, Parellada, Mara, Pries, Katrin, Rivero, Olga, Rutten, Bart P. F., Saiz, Pilar A., Can Saka, Meram, Sanjuan, Julio, Luis Santos, José, Soygür, Haldun, Üçok, Alp, Ulas, Halis, van Os, Jim, Yalinçetin, Berna, Alizadeh, Behrooz Z., van Amelsvoort, Therese, Cahn, Wiepke, de Haan, Lieuwe, Schirmbeck, Frederike, van Os, Jim and Veling, Wim 2024. Clustering schizophrenia genes by their temporal expression patterns aids functional interpretation. Schizophrenia Bulletin: The Journal of Psychoses and Related Disorders 50 (2) , pp. 327-338. 10.1093/schbul/sbad140

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Abstract

Background Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. Study design We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. Study results Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. Conclusions We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other’s effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Oxford University Press
ISSN:	0586-7614
Date of First Compliant Deposit:	31 October 2023
Date of Acceptance:	18 September 2023
Last Modified:	17 Apr 2024 14:09
URI:	https://orca.cardiff.ac.uk/id/eprint/163584

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