title: Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.
abstract: Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.
authors: Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors: Tom
authors: T
authors: Walsh
authors: Jon M
authors: JM
authors: McClellan
authors: Shane E
authors: SE
authors: McCarthy
authors: Anjené M
authors: AM
authors: Addington
authors: Sarah B
authors: SB
authors: Pierce
authors: Greg M
authors: GM
authors: Cooper
authors: Alex S
authors: AS
authors: Nord
authors: Mary
authors: M
authors: Kusenda
authors: Dheeraj
authors: D
authors: Malhotra
authors: Abhishek
authors: A
authors: Bhandari
authors: Sunday M
authors: SM
authors: Stray
authors: Caitlin F
authors: CF
authors: Rippey
authors: Patricia
authors: P
authors: Roccanova
authors: Vlad
authors: V
authors: Makarov
authors: B
authors: B
authors: Lakshmi
authors: Robert L
authors: RL
authors: Findling
authors: Linmarie
authors: L
authors: Sikich
authors: Thomas
authors: T
authors: Stromberg
authors: Barry
authors: B
authors: Merriman
authors: Nitin
authors: N
authors: Gogtay
authors: Philip
authors: P
authors: Butler
authors: Kristen
authors: K
authors: Eckstrand
authors: Laila
authors: L
authors: Noory
authors: Peter
authors: P
authors: Gochman
authors: Robert
authors: R
authors: Long
authors: Zugen
authors: Z
authors: Chen
authors: Sean
authors: S
authors: Davis
authors: Carl
authors: C
authors: Baker
authors: Evan E
authors: EE
authors: Eichler
authors: Paul S
authors: PS
authors: Meltzer
authors: Stanley F
authors: SF
authors: Nelson
authors: Andrew B
authors: AB
authors: Singleton
authors: Ming K
authors: MK
authors: Lee
authors: Judith L
authors: JL
authors: Rapoport
authors: Mary-Claire
authors: MC
authors: King
authors: Jonathan
authors: J
authors: Sebat
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D027341:Excitatory Amino Acid Transporter 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D066247:Receptor, ErbB-4; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: D027341:Excitatory Amino Acid Transporter 1; C493394:SLC1A3 protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4