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

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TitleAutism genome-wide copy number variation reveals ubiquitin and neuronal genes.
Publication TypeJournal Article
Year of Publication2009
AuthorsGlessner, 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, PMA, 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, SFA, Bućan, M, Cook, EH, Buxbaum, JD, Devlin, B, Schellenberg, GD, Hakonarson, H
JournalNature
Volume459
Issue7246
Pagination569-73
Date Published2009 May 28
ISSN1476-4687
KeywordsAutistic Disorder, Case-Control Studies, Cell Adhesion Molecules, Neuronal, Cohort Studies, Europe, Gene Dosage, Gene Regulatory Networks, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genotype, Humans, Neurons, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Reproducibility of Results, Ubiquitin
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.

DOI10.1038/nature07953
Alternate JournalNature
PubMed ID19404257
PubMed Central IDPMC2925224
Grant ListR01 MH064547-05 / MH / NIMH NIH HHS / United States
P50 HD055782 / HD / NICHD NIH HHS / United States
MH64547 / MH / NIMH NIH HHS / United States
U24 MH081810 / MH / NIMH NIH HHS / United States
MH0666730 / MH / NIMH NIH HHS / United States
P50 HD055782-01 / HD / NICHD NIH HHS / United States
M01-RR00064 / RR / NCRR NIH HHS / United States
R01 MH061009-05 / MH / NIMH NIH HHS / United States
M01 RR000064-380591 / RR / NCRR NIH HHS / United States
R01 MH069359-04 / MH / NIMH NIH HHS / United States
R01 NS049261 / NS / NINDS NIH HHS / United States
M01 RR000064-380582 / RR / NCRR NIH HHS / United States
M01 RR000064-36S10579 / RR / NCRR NIH HHS / United States
U54 MH066673-030001 / MH / NIMH NIH HHS / United States
NS049261 / NS / NINDS NIH HHS / United States
P01 HD035476-04 / HD / NICHD NIH HHS / United States
M01 RR000064-36S10582 / RR / NCRR NIH HHS / United States
U19 HD035476-09 / HD / NICHD NIH HHS / United States
R01 MH069359-05 / MH / NIMH NIH HHS / United States
M01 RR000064-37S10582 / RR / NCRR NIH HHS / United States
U24 MH081810-04 / MH / NIMH NIH HHS / United States
M01 RR000064-340579 / RR / NCRR NIH HHS / United States
R01 MH061009-03 / MH / NIMH NIH HHS / United States
R01 MH061009-08 / MH / NIMH NIH HHS / United States
M01 RR000064-350579 / RR / NCRR NIH HHS / United States
M01 RR000064-390579 / RR / NCRR NIH HHS / United States
P50 HD055751-019003 / HD / NICHD NIH HHS / United States
R01 MH069359-02 / MH / NIMH NIH HHS / United States
U54 MH066673-050001 / MH / NIMH NIH HHS / United States
MH061009 / MH / NIMH NIH HHS / United States
R01 MH061009 / MH / NIMH NIH HHS / United States
M01 RR000064-380579 / RR / NCRR NIH HHS / United States
R01 NS049261-01A2 / NS / NINDS NIH HHS / United States
/ / Medical Research Council / United Kingdom
U24 MH081810-02 / MH / NIMH NIH HHS / United States
1U24MH081810 / MH / NIMH NIH HHS / United States
U10 MH066766 / MH / NIMH NIH HHS / United States
R01 MH061009-06 / MH / NIMH NIH HHS / United States
R01 MH061009-01A1 / MH / NIMH NIH HHS / United States
P01 HD035476-04S2 / HD / NICHD NIH HHS / United States
R01 MH064547-01S1 / MH / NIMH NIH HHS / United States
R01 MH069359-01A2 / MH / NIMH NIH HHS / United States
R01 MH061009-07 / MH / NIMH NIH HHS / United States
R01 NS049261-05 / NS / NINDS NIH HHS / United States
R01 MH057881 / MH / NIMH NIH HHS / United States
M01 RR000064-35S10579 / RR / NCRR NIH HHS / United States
U10MH66766-02S1 / MH / NIMH NIH HHS / United States
P01 HD035476-03 / HD / NICHD NIH HHS / United States
U10 MH066766-02S1 / MH / NIMH NIH HHS / United States
R01 MH061009-01A1S1 / MH / NIMH NIH HHS / United States
M01 RR000064-360582 / RR / NCRR NIH HHS / United States
M01 RR000064-35S20591 / RR / NCRR NIH HHS / United States
R01 NS049261-04 / NS / NINDS NIH HHS / United States
U19 HD035476 / HD / NICHD NIH HHS / United States
U19 HD035476-06 / HD / NICHD NIH HHS / United States
U19 HD035476-10 / HD / NICHD NIH HHS / United States
P50 HD055751-02 / HD / NICHD NIH HHS / United States
R01 MH064547-03 / MH / NIMH NIH HHS / United States
U54 MH066673-040001 / MH / NIMH NIH HHS / United States
R01 MH064547-02 / MH / NIMH NIH HHS / United States
P50 HD055751 / HD / NICHD NIH HHS / United States
U19 HD035476-07 / HD / NICHD NIH HHS / United States
U54 MH066673-05 / MH / NIMH NIH HHS / United States
U24 MH081810-01 / MH / NIMH NIH HHS / United States
P50 HD055751-01 / HD / NICHD NIH HHS / United States
U54 MH066673-01A10001 / MH / NIMH NIH HHS / United States
R01 MH064547 / MH / NIMH NIH HHS / United States
M01 RR000064-360579 / RR / NCRR NIH HHS / United States
M01 RR000064-390582 / RR / NCRR NIH HHS / United States
P01 HD035476-04S1 / HD / NICHD NIH HHS / United States
M01 RR000064-370582 / RR / NCRR NIH HHS / United States
P50 HD055751-030002 / HD / NICHD NIH HHS / United States
R01 MH061009-04A1 / MH / NIMH NIH HHS / United States
R01 NS049261-03 / NS / NINDS NIH HHS / United States
R01 MH069359 / MH / NIMH NIH HHS / United States
UL1-RR024134-03 / RR / NCRR NIH HHS / United States
P50 HD055751-04 / HD / NICHD NIH HHS / United States
R01 MH061009-02 / MH / NIMH NIH HHS / United States
R01 MH069359-03 / MH / NIMH NIH HHS / United States
U54 MH066673-020001 / MH / NIMH NIH HHS / United States
R01 MH064547-01 / MH / NIMH NIH HHS / United States
M01 RR000064-370591 / RR / NCRR NIH HHS / United States
P50 HD055751-010002 / HD / NICHD NIH HHS / United States
M01 RR000064-360591 / RR / NCRR NIH HHS / United States
HD35476 / HD / NICHD NIH HHS / United States
R01 MH064547-02S1 / MH / NIMH NIH HHS / United States
HD055782-01 / HD / NICHD NIH HHS / United States
M01 RR000064 / RR / NCRR NIH HHS / United States
M01 RR000064-36S10591 / RR / NCRR NIH HHS / United States
U19 HD035476-08 / HD / NICHD NIH HHS / United States
M01 RR000064-35S20602 / RR / NCRR NIH HHS / United States
MH69359 / MH / NIMH NIH HHS / United States
M01 RR000064-35S10602 / RR / NCRR NIH HHS / United States
R01 MH064547-04 / MH / NIMH NIH HHS / United States
P01 HD035476-05 / HD / NICHD NIH HHS / United States
M01 RR000064-370579 / RR / NCRR NIH HHS / United States
U54 MH066673 / MH / NIMH NIH HHS / United States
M01 RR000064-37S10579 / RR / NCRR NIH HHS / United States
P50 HD055751-03 / HD / NICHD NIH HHS / United States
M01 RR000064-390591 / RR / NCRR NIH HHS / United States
R01 NS049261-02 / NS / NINDS NIH HHS / United States
M01 RR000064-35S10591 / RR / NCRR NIH HHS / United States
UL1 RR024134-03 / RR / NCRR NIH HHS / United States
M01 RR000064-37S10591 / RR / NCRR NIH HHS / United States
UL1 RR024134 / RR / NCRR NIH HHS / United States
HD055751 / HD / NICHD NIH HHS / United States
U24 MH081810-03 / MH / NIMH NIH HHS / United States
M01 RR000064-35S20579 / RR / NCRR NIH HHS / United States
P50 HD055751-020002 / HD / NICHD NIH HHS / United States
P01 HD035476 / HD / NICHD NIH HHS / United States
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