title: Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.
abstract: Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
authors.affiliation: Department of Medicine and Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Watts
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Anne M
authors.initials: AM
authors.lastname: Thornton
authors.forename: Silvia
authors.initials: S
authors.lastname: Casadei
authors.forename: Caitlin
authors.initials: C
authors.lastname: Rippey
authors.forename: Hashem
authors.initials: H
authors.lastname: Shahin
authors.forename: Vishwajit L
authors.initials: VL
authors.lastname: Nimgaonkar
authors.forename: Rodney C P
authors.initials: RC
authors.lastname: Go
authors.forename: Robert M
authors.initials: RM
authors.lastname: Savage
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Jon M
authors.initials: JM
authors.lastname: McClellan
mesh_terms: D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D009154:Mutation; D055495:Neurogenesis; D017397:Prefrontal Cortex / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D060066:Protein Interaction Maps; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D014158:Transcription, Genetic; D059467:Transcriptome
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