Nature 459, 569-573 (28 May 2009) | doi:10.1038/nature07953; Received 13 November 2008; Accepted 27 February 2009; Published online 28 April 2009

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

Joseph T. Glessner1, Kai Wang1, Guiqing Cai2, Olena Korvatska3, Cecilia E. Kim1, Shawn Wood4, Haitao Zhang1, Annette Estes3, Camille W. Brune5, Jonathan P. Bradfield1, Marcin Imielinski1, Edward C. Frackelton1, Jennifer Reichert2, Emily L. Crawford6, Jeffrey Munson3, Patrick M. A. Sleiman1, Rosetta Chiavacci1, Kiran Annaiah1, Kelly Thomas1, Cuiping Hou1, Wendy Glaberson1, James Flory1, Frederick Otieno1, Maria Garris1, Latha Soorya2, Lambertus Klei4, Joseph Piven7, Kacie J. Meyer8, Evdokia Anagnostou2, Takeshi Sakurai2, Rachel M. Game6, Danielle S. Rudd8, Danielle Zurawiecki2, Christopher J. McDougle10, Lea K. Davis8, Judith Miller9, David J. Posey10, Shana Michaels4, Alexander Kolevzon2, Jeremy M. Silverman2, Raphael Bernier3, Susan E. Levy11, Robert T. Schultz11, Geraldine Dawson3, Thomas Owley5, William M. McMahon9, Thomas H. Wassink8, John A. Sweeney5, John I. Nurnberger10, Hilary Coon9, James S. Sutcliffe6, Nancy J. Minshew12, Struan F. A. Grant1,11, Maja Bucan13, Edwin H. Cook5, Joseph D. Buxbaum2,14, Bernie Devlin4, Gerard D. Schellenberg15 & Hakon Hakonarson1,11

  1. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
  2. Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA
  3. University of Washington, Seattle, Washington 98105, USA
  4. Departments of Psychiatry and Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
  5. Institute for Juvenile Research and Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60608, USA
  6. Center for Molecular Neuroscience and Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee 37235, USA
  7. Neurodevelopmental Disorders Research Center and Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27412, USA
  8. University of Iowa, Iowa City, Iowa 52242, USA
  9. University of Utah, Salt Lake City, Utah 84112, USA
  10. Indiana University, Indianapolis, Indiana 46202, USA
  11. Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
  12. Departments of Psychiatry and Neurology, University of Pittsburg School of Medicine, Pittsburg, Pennsylvania 15260, USA
  13. Dept of Genetics, Biology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
  14. Departments of Neuroscience, and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA
  15. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Correspondence to: Gerard D. Schellenberg15Hakon Hakonarson1,11 Correspondence and requests for materials should be addressed to H.H. (Email: hakonarson@chop.edu) or G.D.S (Email: gerardsc@mail.med.upenn.edu).

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1, 2, 3, 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 ASDs5, 6, 7, 8, 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 approx550,000 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 times 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 times 10-3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 times 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.