Title | Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | 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, 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 |
Journal | Nature |
Volume | 459 |
Issue | 7246 |
Pagination | 569-73 |
Date Published | 2009 May 28 |
ISSN | 1476-4687 |
Keywords | Autistic 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. |
DOI | 10.1038/nature07953 |
Alternate Journal | Nature |
PubMed ID | 19404257 |
PubMed Central ID | PMC2925224 |
Grant List | R01 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 T32 GM008629 / GM / NIGMS 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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