Clustering Schizophrenia Genes by Their Temporal Expression Patterns Aids Functional Interpretation
Authors: 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 , Richards Alexander L , Steen Nils Eiel , Djurovic Srdjan , Westlye Lars T , Andreassen Ole A , Kaufmann Tobias ,   Genetic Risk and Outcome of Psychosis investigators (GROUP), Aguilar Eduardo J , Akdede Berna , Alptekin Köksal , Altınyazar Vesile , Amoretti Silvia , Andric-Petrovic Sanja , Arango Celso , Arrojo Manuel , Atbaşoğlu Cem , Bernardo Miguel , Binbay Tolga , Bobes Julio , Cankurtaran Eylem Şahin , Carracedo Angel , Cihan Burçin , Delespaul Philippe , García-Portilla Maria Paz , González-Peñas Javier , Guloksuz Sinan , Gümüş-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 , Ulaş Halis , van Os Jim , Yalınçetin Berna ,   European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 6 (EU-GEI WP6), Alizadeh Behrooz Z , van Amelsvoort Therese , Cahn Wiepke , de Haan Lieuwe , Schirmbeck Frederike , van Os Jim , Veling Wim 
Published: October 2023

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.