Functional impact of global rare copy number variation in autism spectrum disorders.
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Pinto
Dalila
D
The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Pagnamenta
Alistair T
AT
Klei
Lambertus
L
Anney
Richard
R
Merico
Daniele
D
Regan
Regina
R
Conroy
Judith
J
Magalhaes
Tiago R
TR
Correia
Catarina
C
Abrahams
Brett S
BS
Almeida
Joana
J
Bacchelli
Elena
E
Bader
Gary D
GD
Bailey
Anthony J
AJ
Baird
Gillian
G
Battaglia
Agatino
A
Berney
Tom
T
Bolshakova
Nadia
N
Bölte
Sven
S
Bolton
Patrick F
PF
Bourgeron
Thomas
T
Brennan
Sean
S
Brian
Jessica
J
Bryson
Susan E
SE
Carson
Andrew R
AR
Casallo
Guillermo
G
Casey
Jillian
J
Chung
Brian H Y
BH
Cochrane
Lynne
L
Corsello
Christina
C
Crawford
Emily L
EL
Crossett
Andrew
A
Cytrynbaum
Cheryl
C
Dawson
Geraldine
G
de Jonge
Maretha
M
Delorme
Richard
R
Drmic
Irene
I
Duketis
Eftichia
E
Duque
Frederico
F
Estes
Annette
A
Farrar
Penny
P
Fernandez
Bridget A
BA
Folstein
Susan E
SE
Fombonne
Eric
E
Freitag
Christine M
CM
Gilbert
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J
Gillberg
Christopher
C
Glessner
Joseph T
JT
Goldberg
Jeremy
J
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Andrew
A
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Jonathan
J
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Stephen J
SJ
Hakonarson
Hakon
H
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Elizabeth A
EA
Hill
Matthew
M
Holt
Richard
R
Howe
Jennifer L
JL
Hughes
Gillian
G
Hus
Vanessa
V
Igliozzi
Roberta
R
Kim
Cecilia
C
Klauck
Sabine M
SM
Kolevzon
Alexander
A
Korvatska
Olena
O
Kustanovich
Vlad
V
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Clara M
CM
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Janine A
JA
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Magdalena
M
Leboyer
Marion
M
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Ann
A
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Bennett L
BL
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Anath C
AC
Liu
Xiao-Qing
XQ
Lord
Catherine
C
Lotspeich
Linda
L
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Sabata C
SC
Maestrini
Elena
E
Mahoney
William
W
Mantoulan
Carine
C
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Christian R
CR
McConachie
Helen
H
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Christopher J
CJ
McGrath
Jane
J
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William M
WM
Merikangas
Alison
A
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O
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Nancy J
NJ
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Ghazala K
GK
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Jeff
J
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Stanley F
SF
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Carolyn
C
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G
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K
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JR
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Barbara
B
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Tara
T
Pickles
Andrew
A
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Marion
M
Piven
Joseph
J
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Chris P
CP
Posey
David J
DJ
Poustka
Annemarie
A
Poustka
Fritz
F
Prasad
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A
Ragoussis
Jiannis
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Katy
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Wendy
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Bernadette
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Michael L
ML
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LJ
Rice
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JP
Salt
Jeff
J
Sansom
Katherine
K
Sato
Daisuke
D
Segurado
Ricardo
R
Sequeira
Ana F
AF
Senman
Lili
L
Shah
Naisha
N
Sheffield
Val C
VC
Soorya
Latha
L
Sousa
Inês
I
Stein
Olaf
O
Sykes
Nuala
N
Stoppioni
Vera
V
Strawbridge
Christina
C
Tancredi
Raffaella
R
Tansey
Katherine
K
Thiruvahindrapduram
Bhooma
B
Thompson
Ann P
AP
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Susanne
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Tryfon
Ana
A
Tsiantis
John
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Van Engeland
Herman
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Vincent
John B
JB
Volkmar
Fred
F
Wallace
Simon
S
Wang
Kai
K
Wang
Zhouzhi
Z
Wassink
Thomas H
TH
Webber
Caleb
C
Weksberg
Rosanna
R
Wing
Kirsty
K
Wittemeyer
Kerstin
K
Wood
Shawn
S
Wu
Jing
J
Yaspan
Brian L
BL
Zurawiecki
Danielle
D
Zwaigenbaum
Lonnie
L
Buxbaum
Joseph D
JD
Cantor
Rita M
RM
Cook
Edwin H
EH
Coon
Hilary
H
Cuccaro
Michael L
ML
Devlin
Bernie
B
Ennis
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S
Gallagher
Louise
L
Geschwind
Daniel H
DH
Gill
Michael
M
Haines
Jonathan L
JL
Hallmayer
Joachim
J
Miller
Judith
J
Monaco
Anthony P
AP
Nurnberger
John I
JI
Paterson
Andrew D
AD
Pericak-Vance
Margaret A
MA
Schellenberg
Gerard D
GD
Szatmari
Peter
P
Vicente
Astrid M
AM
Vieland
Veronica J
VJ
Wijsman
Ellen M
EM
Scherer
Stephen W
SW
Sutcliffe
James S
JS
Betancur
Catalina
C
D016022:Case-Control Studies; D002465:Cell Movement; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D019610:Cytoprotection; D056915:DNA Copy Number Variations / Q000235:genetics*; D005060:Europe / Q000208:ethnology; D018628:Gene Dosage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D015398:Signal Transduction; D012919:Social Behavior