Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.
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.
Walsh
Tom
T
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
McClellan
Jon M
JM
McCarthy
Shane E
SE
Addington
Anjené M
AM
Pierce
Sarah B
SB
Cooper
Greg M
GM
Nord
Alex S
AS
Kusenda
Mary
M
Malhotra
Dheeraj
D
Bhandari
Abhishek
A
Stray
Sunday M
SM
Rippey
Caitlin F
CF
Roccanova
Patricia
P
Makarov
Vlad
V
Lakshmi
B
B
Findling
Robert L
RL
Sikich
Linmarie
L
Stromberg
Thomas
T
Merriman
Barry
B
Gogtay
Nitin
N
Butler
Philip
P
Eckstrand
Kristen
K
Noory
Laila
L
Gochman
Peter
P
Long
Robert
R
Chen
Zugen
Z
Davis
Sean
S
Baker
Carl
C
Eichler
Evan E
EE
Meltzer
Paul S
PS
Nelson
Stanley F
SF
Singleton
Andrew B
AB
Lee
Ming K
MK
Rapoport
Judith L
JL
King
Mary-Claire
MC
Sebat
Jonathan
J
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
D027341:Excitatory Amino Acid Transporter 1; C493394:SLC1A3 protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4