Autism genome-wide copy number variation reveals ubiquitin and neuronal genes by 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, 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 in Nature (2009).

[PMID: 19404257] PubMed


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.

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