Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
Glessner
Joseph T
JT
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Wang
Kai
K
Cai
Guiqing
G
Korvatska
Olena
O
Kim
Cecilia E
CE
Wood
Shawn
S
Zhang
Haitao
H
Estes
Annette
A
Brune
Camille W
CW
Bradfield
Jonathan P
JP
Imielinski
Marcin
M
Frackelton
Edward C
EC
Reichert
Jennifer
J
Crawford
Emily L
EL
Munson
Jeffrey
J
Sleiman
Patrick M A
PM
Chiavacci
Rosetta
R
Annaiah
Kiran
K
Thomas
Kelly
K
Hou
Cuiping
C
Glaberson
Wendy
W
Flory
James
J
Otieno
Frederick
F
Garris
Maria
M
Soorya
Latha
L
Klei
Lambertus
L
Piven
Joseph
J
Meyer
Kacie J
KJ
Anagnostou
Evdokia
E
Sakurai
Takeshi
T
Game
Rachel M
RM
Rudd
Danielle S
DS
Zurawiecki
Danielle
D
McDougle
Christopher J
CJ
Davis
Lea K
LK
Miller
Judith
J
Posey
David J
DJ
Michaels
Shana
S
Kolevzon
Alexander
A
Silverman
Jeremy M
JM
Bernier
Raphael
R
Levy
Susan E
SE
Schultz
Robert T
RT
Dawson
Geraldine
G
Owley
Thomas
T
McMahon
William M
WM
Wassink
Thomas H
TH
Sweeney
John A
JA
Nurnberger
John I
JI
Coon
Hilary
H
Sutcliffe
James S
JS
Minshew
Nancy J
NJ
Grant
Struan F A
SF
Bucan
Maja
M
Cook
Edwin H
EH
Buxbaum
Joseph D
JD
Devlin
Bernie
B
Schellenberg
Gerard D
GD
Hakonarson
Hakon
H
D001321:Autistic Disorder / Q000235:genetics*; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D015331:Cohort Studies; D005060:Europe / Q000208:ethnology; D018628:Gene Dosage / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D025801:Ubiquitin / Q000378:metabolism*
D015816:Cell Adhesion Molecules, Neuronal; D025801:Ubiquitin