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PMID: 19404257 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

Nature ·Vol. 459 ·No. 7246 ·2009-05-28 ·Pages 569-73

Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H

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.

MeSH Terms
Autistic Disorder/genetics Case-Control Studies Cell Adhesion Molecules, Neuronal/genetics Cohort Studies Europe/ethnology Gene Dosage/genetics Gene Regulatory Networks/genetics Genetic Predisposition to Disease/genetics Genetic Variation/genetics Genome, Human/genetics Genotype Humans Neurons/metabolism Polymerase Chain Reaction Polymorphism, Single Nucleotide/genetics Reproducibility of Results Ubiquitin/metabolism
Chemicals
Cell Adhesion Molecules, Neuronal Ubiquitin
Authors & Affiliations
59 authors, click to expand affiliations / ORCID
Glessner Joseph T
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Wang Kai
Cai Guiqing
Korvatska Olena
Kim Cecilia E
Wood Shawn
Zhang Haitao
Estes Annette
Brune Camille W
Bradfield Jonathan P
Imielinski Marcin
Frackelton Edward C
Reichert Jennifer
Crawford Emily L
Munson Jeffrey
Sleiman Patrick M A
Chiavacci Rosetta
Annaiah Kiran
Thomas Kelly
Hou Cuiping
Glaberson Wendy
Flory James
Otieno Frederick
Garris Maria
Soorya Latha
Klei Lambertus
Piven Joseph
Meyer Kacie J
Anagnostou Evdokia
Sakurai Takeshi
Game Rachel M
Rudd Danielle S
Zurawiecki Danielle
McDougle Christopher J
Davis Lea K
Miller Judith
Posey David J
Michaels Shana
Kolevzon Alexander
Silverman Jeremy M
Bernier Raphael
Levy Susan E
Schultz Robert T
Dawson Geraldine
Owley Thomas
McMahon William M
Wassink Thomas H
Sweeney John A
Nurnberger John I
Coon Hilary
Sutcliffe James S
Minshew Nancy J
Grant Struan F A
Bucan Maja
Cook Edwin H
Buxbaum Joseph D
Devlin Bernie
Schellenberg Gerard D
Hakonarson Hakon
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature07953
Published
2009-05-28
Epub
2009-00-28
Pages
569-73
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2925224
Subset
IM
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PubMed source DOI: 10.1038/nature07953 PMC Full Text View journal details
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