title: Strong synaptic transmission impact by copy number variations in schizophrenia.
abstract: Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 x 10(-7)). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.forename: Nagahide
authors.initials: N
authors.lastname: Takahashi
authors.forename: Anthony
authors.initials: A
authors.lastname: Albano
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Patrick M A
authors.initials: PM
authors.lastname: Sleiman
authors.forename: James H
authors.initials: JH
authors.lastname: Flory
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.forename: Edward C
authors.initials: EC
authors.lastname: Frackelton
authors.forename: Rosetta
authors.initials: R
authors.lastname: Chiavacci
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Thomas
authors.forename: Maria
authors.initials: M
authors.lastname: Garris
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Otieno
authors.forename: Michael
authors.initials: M
authors.lastname: Davidson
authors.forename: Mark
authors.initials: M
authors.lastname: Weiser
authors.forename: Abraham
authors.initials: A
authors.lastname: Reichenberg
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Davis
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Friedman
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D015331:Cohort Studies; D056915:DNA Copy Number Variations; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*; D009435:Synaptic Transmission