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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study design<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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\u2019s effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/schbul\/sbad140","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T16:08:53Z","timestamp":1695053333000},"page":"327-338","source":"Crossref","is-referenced-by-count":5,"title":["Clustering Schizophrenia Genes by Their Temporal Expression Patterns Aids Functional Interpretation"],"prefix":"10.1093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0466-386X","authenticated-orcid":false,"given":"Dennis","family":"van der Meer","sequence":"first","affiliation":[{"name":"Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital & Institute of Clinical Medicine, University of Oslo , Oslo , Norway"},{"name":"Faculty of Health, 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Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Fernandez-Cabello","sequence":"additional","affiliation":[{"name":"Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital & Institute of Clinical Medicine, University of Oslo , Oslo , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Shadrin","sequence":"additional","affiliation":[{"name":"Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital & Institute of Clinical Medicine, University of Oslo , Oslo , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3761-5215","authenticated-orcid":false,"given":"Olav B","family":"Smeland","sequence":"additional","affiliation":[{"name":"Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), 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Jebsen Centre for Neurodevelopmental Disorders, University of Oslo , Oslo , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole A","family":"Andreassen","sequence":"additional","affiliation":[{"name":"Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital & Institute of Clinical Medicine, University of Oslo , Oslo , Norway"},{"name":"K.G. 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