Strong synaptic transmission impact by copy number variations in schizophrenia.
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.
Glessner
Joseph T
JT
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Reilly
Muredach P
MP
Kim
Cecilia E
CE
Takahashi
Nagahide
N
Albano
Anthony
A
Hou
Cuiping
C
Bradfield
Jonathan P
JP
Zhang
Haitao
H
Sleiman
Patrick M A
PM
Flory
James H
JH
Imielinski
Marcin
M
Frackelton
Edward C
EC
Chiavacci
Rosetta
R
Thomas
Kelly A
KA
Garris
Maria
M
Otieno
Frederick G
FG
Davidson
Michael
M
Weiser
Mark
M
Reichenberg
Abraham
A
Davis
Kenneth L
KL
Friedman
Joseph I
JI
Cappola
Thomas P
TP
Margulies
Kenneth B
KB
Rader
Daniel J
DJ
Grant
Struan F A
SF
Buxbaum
Joseph D
JD
Gur
Raquel E
RE
Hakonarson
Hakon
H
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