title: Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.
abstract: 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.
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Olena
authors.initials: O
authors.lastname: Korvatska
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.forename: Shawn
authors.initials: S
authors.lastname: Wood
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Annette
authors.initials: A
authors.lastname: Estes
authors.forename: Camille W
authors.initials: CW
authors.lastname: Brune
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.forename: Edward C
authors.initials: EC
authors.lastname: Frackelton
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reichert
authors.forename: Emily L
authors.initials: EL
authors.lastname: Crawford
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Munson
authors.forename: Patrick M A
authors.initials: PM
authors.lastname: Sleiman
authors.forename: Rosetta
authors.initials: R
authors.lastname: Chiavacci
authors.forename: Kiran
authors.initials: K
authors.lastname: Annaiah
authors.forename: Kelly
authors.initials: K
authors.lastname: Thomas
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Wendy
authors.initials: W
authors.lastname: Glaberson
authors.forename: James
authors.initials: J
authors.lastname: Flory
authors.forename: Frederick
authors.initials: F
authors.lastname: Otieno
authors.forename: Maria
authors.initials: M
authors.lastname: Garris
authors.forename: Latha
authors.initials: L
authors.lastname: Soorya
authors.forename: Lambertus
authors.initials: L
authors.lastname: Klei
authors.forename: Joseph
authors.initials: J
authors.lastname: Piven
authors.forename: Kacie J
authors.initials: KJ
authors.lastname: Meyer
authors.forename: Evdokia
authors.initials: E
authors.lastname: Anagnostou
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Game
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Rudd
authors.forename: Danielle
authors.initials: D
authors.lastname: Zurawiecki
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McDougle
authors.forename: Lea K
authors.initials: LK
authors.lastname: Davis
authors.forename: Judith
authors.initials: J
authors.lastname: Miller
authors.forename: David J
authors.initials: DJ
authors.lastname: Posey
authors.forename: Shana
authors.initials: S
authors.lastname: Michaels
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolevzon
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.forename: Susan E
authors.initials: SE
authors.lastname: Levy
authors.forename: Robert T
authors.initials: RT
authors.lastname: Schultz
authors.forename: Geraldine
authors.initials: G
authors.lastname: Dawson
authors.forename: Thomas
authors.initials: T
authors.lastname: Owley
authors.forename: William M
authors.initials: WM
authors.lastname: McMahon
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Wassink
authors.forename: John A
authors.initials: JA
authors.lastname: Sweeney
authors.forename: John I
authors.initials: JI
authors.lastname: Nurnberger
authors.forename: Hilary
authors.initials: H
authors.lastname: Coon
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Minshew
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Maja
authors.initials: M
authors.lastname: Bucan
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: 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*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D025801:Ubiquitin