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

被引：1016

作者：

Glessner, Joseph T. ^{[1
]}

Wang, Kai ^{[1
]}

Cai, Guiqing ^{[2
]}

Korvatska, Olena ^{[3
]}

Kim, Cecilia E. ^{[1
]}

Wood, Shawn ^{[4
,5
]}

Zhang, Haitao ^{[1
]}

Estes, Annette ^{[3
]}

Brune, Camille W. ^{[6
,7
]}

Bradfield, Jonathan P. ^{[1
]}

Imielinski, Marcin ^{[1
]}

Frackelton, Edward C. ^{[1
]}

Reichert, Jennifer ^{[2
]}

Crawford, Emily L. ^{[8
,9
]}

Munson, Jeffrey ^{[3
]}

Sleiman, Patrick M. A. ^{[1
]}

Chiavacci, Rosetta ^{[1
]}

Annaiah, Kiran ^{[1
]}

Thomas, Kelly ^{[1
]}

Hou, Cuiping ^{[1
]}

Glaberson, Wendy ^{[1
]}

Flory, James ^{[1
]}

Otieno, Frederick ^{[1
]}

Garris, Maria ^{[1
]}

Soorya, Latha ^{[2
]}

Klei, Lambertus ^{[4
,5
]}

Piven, Joseph ^{[10
,11
]}

Meyer, Kacie J. ^{[12
]}

Anagnostou, Evdokia ^{[2
]}

Sakurai, Takeshi ^{[2
]}

Game, Rachel M. ^{[8
,9
]}

Rudd, Danielle S. ^{[12
]}

Zurawiecki, Danielle ^{[2
]}

McDougle, Christopher J. ^{[14
]}

Davis, Lea K. ^{[12
]}

Miller, Judith ^{[13
]}

Posey, David J. ^{[14
]}

Michaels, Shana ^{[4
,5
]}

Kolevzon, Alexander ^{[2
]}

Silverman, Jeremy M. ^{[2
]}

Bernier, Raphael ^{[3
]}

Levy, Susan E. ^{[15
]}

Schultz, Robert T. ^{[15
]}

Dawson, Geraldine ^{[3
]}

Owley, Thomas ^{[6
,7
]}

McMahon, William M. ^{[13
]}

Wassink, Thomas H. ^{[12
]}

Sweeney, John A. ^{[6
,7
]}

Nurnberger, John I., Jr. ^{[14
]}

Coon, Hilary ^{[13
]}

机构：

[1] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[2] Mt Sinai Sch Med, Dept Psychiat, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[3] Univ Washington, Seattle, WA 98105 USA

[4] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA

[5] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15260 USA

[6] Univ Illinois, Inst Juvenile Res, Chicago, IL 60608 USA

[7] Univ Illinois, Dept Psychiat, Chicago, IL 60608 USA

[8] Vanderbilt Univ, Ctr Mol Neurosci, Nashville, TN 37235 USA

[9] Vanderbilt Univ, Vanderbilt Kennedy Ctr, Nashville, TN 37235 USA

[10] Univ N Carolina, Neurodev Disorders Res Ctr, Greensboro, NC 27412 USA

[11] Univ N Carolina, Dept Psychiat, Greensboro, NC 27412 USA

[12] Univ Iowa, Iowa City, IA 52242 USA

[13] Univ Utah, Salt Lake City, UT 84112 USA

[14] Indiana Univ, Indianapolis, IN 46202 USA

[15] Univ Penn, Sch Med, Dept Pediat, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[16] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA

[17] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15260 USA

[18] Univ Penn, Sch Med, Dept Genet Biol & Biostat, Philadelphia, PA 19104 USA

[19] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA

[20] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA

[21] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

来源：

NATURE | 2009年 / 459卷 / 7246期

基金：

英国医学研究理事会;

关键词：

SPECTRUM DISORDER; SUSCEPTIBILITY GENE; MUTATIONS; ASSOCIATION; NEUROLIGINS; MIGRATION; LINKAGE;

D O I：

10.1038/nature07953

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins(1-4). 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(5-9). 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 similar to 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.

引用

页码：569 / 573

页数：5

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