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 Bjerkehagen; Ehrhart, Friederike; Guloksuz, Sinan; Pries, Lotta-Katrin; Lin, Bochao Danae; Rutten, Bart P F; Van Os, Jim; O’Donovan, Michael; Richards, Alexander L.; Steen, Nils Eiel; Djurovic, Srdjan; Westlye, Lars Tjelta; Andreassen, Ole; Kaufmann, Tobias Herbert
Journal article, Peer reviewed
Published version
View/ Open
Date
2024Metadata
Show full item recordCollections
- Department of Clinical Science [2397]
- Registrations from Cristin [10473]
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.