TY - JOUR
T1 - Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism
AU - Sanders, Stephan J.
AU - Ercan-Sencicek, A. Gulhan
AU - Hus, Vanessa
AU - Luo, Rui
AU - Murtha, Michael T.
AU - Moreno-De-Luca, Daniel
AU - Chu, Su H.
AU - Moreau, Michael P.
AU - Gupta, Abha R.
AU - Thomson, Susanne A.
AU - Mason, Christopher E.
AU - Bilguvar, Kaya
AU - Celestino-Soper, Patricia B.S.
AU - Choi, Murim
AU - Crawford, Emily L.
AU - Davis, Lea
AU - Davis Wright, Nicole R.
AU - Dhodapkar, Rahul M.
AU - DiCola, Michael
AU - DiLullo, Nicholas M.
AU - Fernandez, Thomas V.
AU - Fielding-Singh, Vikram
AU - Fishman, Daniel O.
AU - Frahm, Stephanie
AU - Garagaloyan, Rouben
AU - Goh, Gerald S.
AU - Kammela, Sindhuja
AU - Klei, Lambertus
AU - Lowe, Jennifer K.
AU - Lund, Sabata C.
AU - McGrew, Anna D.
AU - Meyer, Kyle A.
AU - Moffat, William J.
AU - Murdoch, John D.
AU - O'Roak, Brian J.
AU - Ober, Gordon T.
AU - Pottenger, Rebecca S.
AU - Raubeson, Melanie J.
AU - Song, Youeun
AU - Wang, Qi
AU - Yaspan, Brian L.
AU - Yu, Timothy W.
AU - Yurkiewicz, Ilana R.
AU - Beaudet, Arthur L.
AU - Cantor, Rita M.
AU - Curland, Martin
AU - Grice, Dorothy E.
AU - Günel, Murat
AU - Lifton, Richard P.
AU - Mane, Shrikant M.
AU - Martin, Donna M.
AU - Shaw, Chad A.
AU - Sheldon, Michael
AU - Tischfield, Jay A.
AU - Walsh, Christopher A.
AU - Morrow, Eric M.
AU - Ledbetter, David H.
AU - Fombonne, Eric
AU - Lord, Catherine
AU - Martin, Christa Lese
AU - Brooks, Andrew I.
AU - Sutcliffe, James S.
AU - Cook, Edwin H.
AU - Geschwind, Daniel
AU - Roeder, Kathryn
AU - Devlin, Bernie
AU - State, Matthew W.
N1 - Funding Information:
We are most grateful to all of the families at the participating Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC) sites. This work was supported by a grant from the Simons Foundation (SFARI 124827). C.A. Walsh and R.P. Lifton are Investigators of the Howard Hughes Medical Institute. We wish to thank the SSC principal investigators A.L. Beaudet, R. Bernier, J. Constantino, E.H. Cook, Jr., E. Fombonne, D. Geschwind, D.E. Grice, A. Klin, D.H. Ledbetter, C. Lord, C.L. Martin, D.M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M.W. State, W. Stone, J.S. Sutcliffe, C.A. Walsh, and E. Wijsman; the coordinators and staff at the SSC sites; the SFARI staff (M. Greenup and S. Johnson); R. Smith and Z. Galfayan at Microangelo Associates for bioinformatics support; Prometheus Research; the Yale Center of Genomic Analysis staff, in particular S. Umlauf and C. Castaldi; T. Brooks-Boone and M. Wojciechowski for their help in administering the project at Yale; and J. Krystal, G.D. Fischbach, A. Packer, J. Spiro, and M. Benedetti for their suggestions throughout and very helpful comments during the preparation of this manuscript. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org . D.H. Ledbetter acts as a consultant for Roche Diagnostics and BioReference Laboratories; M.W. State, R.P. Lifton, and B.J. O'Roak hold a patent relating to the gene CNTNAP2.
PY - 2011/6/9
Y1 - 2011/6/9
N2 - We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10-7). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
AB - We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10-7). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
UR - http://www.scopus.com/inward/record.url?scp=79958074870&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2011.05.002
DO - 10.1016/j.neuron.2011.05.002
M3 - Article
C2 - 21658581
AN - SCOPUS:79958074870
SN - 0896-6273
VL - 70
SP - 863
EP - 885
JO - Neuron
JF - Neuron
IS - 5
ER -