Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.
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DOI：
10.1038/nature07953
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发表时间：
2009-05-28
期刊：
影响因子：
64.8
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
--
作者：
Glessner, Joseph T.;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., Jr.;Coon, Hilary;Sutcliffe, James S.;Minshew, Nancy J.;Grant, Struan F. A.;Bucan, Maja;Cook, Edwin H., Jr.;Buxbaum, Joseph D.;Devlin, Bernie;Schellenberg, Gerard D.;Hakonarson, Hakon
自闭症谱系障碍（ASD）是具有复杂遗传起源的儿童神经发育障碍。以前的研究集中在候选基因或基因组区域，已经确定了几个拷贝数变异（CNV）与ASD风险增加有关。在这里，我们介绍了一项全基因组CNV研究的结果，该研究对859例ASD病例和1，409名欧洲血统的健康儿童进行了基因分型，使用~ 550，000个单核苷酸多态性标记，试图全面识别CNV赋予ASD易感性。在一个由1，336例ASD病例和1，110例欧洲血统对照组成的独立队列中评估了阳性结果。除了先前报道的ASD候选基因，如NRXN 1（参考文献）和CNTN 4（参考文献），几个新的易感基因编码神经元细胞粘附分子，包括NLGN 1和ASTN 2，与对照组相比，ASD病例中的CNV富集（P = 9.5 × 10−3）。此外，参与泛素途径的基因（包括UBE 3A、PARK 2、RFWD 2和FBXO 40）内或周围的CNV受到对照组中未观察到的CNV的影响（P = 3.3 × 10−3）。我们还鉴定了互补DNA AK 123120上游的55个重复酶（P = 3.6 × 10−6）。虽然这些变异可能是个别罕见的，他们的目标基因参与神经元细胞粘附或泛素降解，表明这两个重要的基因网络表达的中枢神经系统内可能有助于遗传易感性的ASD。
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 ~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.) and CNTN4 (refs), 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 × 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 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 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.
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