Functional impact of global rare copy number variation in autism spectrum disorders : Nature : Nature Publishing Group

Functional impact of global rare copy number variation in autism spectrum disorders

Dalila Pinto,Alistair T. Pagnamenta,Lambertus Klei,Richard Anney,Daniele Merico,Regina Regan,Judith Conroy,Tiago R. Magalhaes,Catarina Correia,Brett S. Abrahams,Joana Almeida,Elena Bacchelli,Gary D. Bader,Anthony J. Bailey,Gillian Baird,Agatino Battaglia,Tom Berney,Nadia Bolshakova,Sven Bölte,Patrick F. Bolton,Thomas Bourgeron,Sean Brennan,Jessica Brian,Susan E. Bryson,Andrew R. Carson, Guillermo Casallo, Jillian Casey, Brian H.Y. Chung, Lynne Cochrane,
Christina Corsello, Emily L. Crawford, Andrew Crossett, Cheryl Cytrynbaum, Geraldine Dawson,
Maretha de Jonge, Richard Delorme, Irene Drmic, Eftichia Duketis, Frederico Duque, Annette Estes, Penny Farrar, Bridget A. Fernandez, Susan E. Folstein, Eric Fombonne, Christine M. Freitag, John Gilbert, Christopher Gillberg, Joseph T. Glessner, Jeremy Goldberg, Andrew Green,
Jonathan Green, Stephen J. Guter, Hakon Hakonarson, Elizabeth A. Heron, Matthew Hill, Richard Holt, Jennifer L. Howe, Gillian Hughes, Vanessa Hus, Roberta Igliozzi, Cecilia Kim, Sabine M. Klauck, Alexander Kolevzon, Olena Korvatska, Vlad Kustanovich, Clara M. Lajonchere, Janine A. Lamb, Magdalena Laskawiec, Marion Leboyer, Ann Le Couteur, Bennett L. Leventhal, Anath C. Lionel, Xiao-Qing Liu, Catherine Lord, Linda Lotspeich, Sabata C. Lund, Elena Maestrini,
William Mahoney, Carine Mantoulan, Christian R. Marshall, Helen McConachie, Christopher J. McDougle, Jane McGrath, William M. McMahon, Alison Merikangas, Ohsuke Migita, Nancy J. Minshew,
Ghazala K. Mirza, Jeff Munson, Stanley F. Nelson, Carolyn Noakes, Abdul Noor, Gudrun Nygren,
Guiomar Oliveira, Katerina Papanikolaou, Jeremy R. Parr, Barbara Parrini, Tara Paton, Andrew Pickles, Marion Pilorge, Joseph Piven, Chris P. Ponting, David J. Posey, Annemarie Poustka,
Fritz Poustka, Aparna Prasad, Jiannis Ragoussis, Katy Renshaw, Jessica Rickaby, Wendy Roberts,
Kathryn Roeder, Bernadette Roge, Michael L. Rutter, Laura J. Bierut, John P. Rice, Jeff Salt,
Katherine Sansom, Daisuke Sato, Ricardo Segurado, Ana F. Sequeira, Lili Senman, Naisha Shah,
Val C. Sheffield, Latha Soorya, Inês Sousa, Olaf Stein, Nuala Sykes, Vera Stoppioni, Christina Strawbridge, Raffaella Tancredi, Katherine Tansey, Bhooma Thiruvahindrapduram, Ann P. Thompson,
Susanne Thomson, Ana Tryfon, John Tsiantis, Herman Van Engeland, John B. Vincent, Fred Volkmar,
Simon Wallace, & Catalina Betancur et al.

Journal name: Nature

Year published: (2010)

DOI: doi:10.1038/nature09146
Received03 December 2009
Accepted07 May 2010
Published online09 June 2010

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable (~90%)3, the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

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Figures at a glance
leftFigure 1: CNV discovery and characterization.
Comprehensive procedures were used to identify the rare CNV data set (boxed). Dashed arrows indicate CNVs not included in downstream analyses. Labels a–f are as follows: a, SNP and intensity quality control (QC) with ancestry estimation; b, QC for CNV calls; c, pilot validation experiments using quantitative PCR were used to evaluate the false discovery rate; d, rare CNVs in samples of European ancestry were defined as ≥30 kb in size and present in the total sample set at a frequency <1%. A total of 70 out of 996 (17%) of ASD cases were analysed on different lower-resolution arrays in previous studies9, 10, 28. Label e indicates that all CNVs were computationally verified and at least 40% of case CNVs were also experimentally validated by qPCR and/or independent Agilent or other SNP microarrays; f, 3,677 additional European ancestry controls were used to test specific loci from the primary burden analyses. Additional details are in the Methods and Supplementary Information. ID, intellectual disability.

Figure 2: CNV burden in known ASD and/or intellectual disability genes.
a, Proportion of samples with CNVs overlapping genes and loci known to be associated in ASD with or without intellectual disability (ID) or intellectual disability only, as well as published candidate genes and loci for ASD (Supplementary Table 9). To select for CNVs with maximal impact, they needed to intersect genes and overlap the target loci by ≥50% of their length. Fisher’s exact test P-values for significant differences (P ≤ 0.05, one tailed) are shown. NS, not significant. b, Enrichment analysis for genes overlapped by rare CNVs in cases compared to controls for the three gene sets in a, relative to the whole genome. Odds ratio and 95% confidence intervals are given for each gene set. Empirical P-values for gene-set enrichment are indicated above each odds ratio. All P-values <0.1 are listed.
Figure 3: A functional map of ASD.

Functional impact of global rare copy number variation in autism spectrum disorders : Nature : Nature Publishing Group

Nature (2010); doi:10.1038/nature09146
open here or above:
http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature09146.html


Centro Seaver para la Investigación y el Tratamiento del Autismo
http://www.mssm.edu/research/centers/seaver-autism-center

Consorcio Proyecto Genoma del Autismo
http://www.autismgenome.org/

Hospital Monte Sinai
http://www.mountsinai.org/

Nature