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. 2010 Jul 15;466(7304):368-72.
doi: 10.1038/nature09146. Epub 2010 Jun 9.

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

Dalila Pinto  1 , 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, Kai Wang, Zhouzhi Wang, Thomas H Wassink, Caleb Webber, Rosanna Weksberg, Kirsty Wing, Kerstin Wittemeyer, Shawn Wood, Jing Wu, Brian L Yaspan, Danielle Zurawiecki, Lonnie Zwaigenbaum, Joseph D Buxbaum, Rita M Cantor, Edwin H Cook, Hilary Coon, Michael L Cuccaro, Bernie Devlin, Sean Ennis, Louise Gallagher, Daniel H Geschwind, Michael Gill, Jonathan L Haines, Joachim Hallmayer, Judith Miller, Anthony P Monaco, John I Nurnberger Jr, Andrew D Paterson, Margaret A Pericak-Vance, Gerard D Schellenberg, Peter Szatmari, Astrid M Vicente, Veronica J Vieland, Ellen M Wijsman, Stephen W Scherer, James S Sutcliffe, Catalina Betancur
Affiliations

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

Dalila Pinto et al. Nature. .

Abstract

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 behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), 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 x 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

Figure 1
Figure 1. CNV discovery and characterization
Comprehensive procedures were used to identify the rare CNV dataset (boxed). Dashed arrows indicate CNVs not included in downstream analyses. SNP and intensity quality control (QC) with ancestry estimation. QC for CNV calls. Pilot validation experiments using quantitative-PCR were used to evaluate the false discovery-rate. Rare CNVs in samples of EA ancestry were defined as 30 kb in size and present in the total sample set at a frequency <1%. 70/996 (17%) of ASD cases were analyzed on different lower-resolution arrays in previous studies,,. 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. 3,677 additional EA controls were used to test specific loci from the primary burden analyses. Additional details are in the Methods Summary and Supplementary Information
Figure 2
Figure 2. CNV burden in known ASD and/or ID genes
a, Proportion of samples with CNVs overlapping genes and loci known to be associated in ASD with or without ID or ID 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. b, enrichment analysis for genes overlapped by rare CNVs in cases compared to controls for the three gene-sets in panel a, relative to the whole genome. Odds ratio (OR) and 95% confidence intervals are given for each gene set. Empirical P-values for gene-set enrichment are indicated above each OR. All P-values <0.1 are listed.
Figure 3
Figure 3. A functional map of ASD
Enrichment results were mapped into a network of gene-sets (nodes) related by mutual overlap (edges), where the color (red, blue, or yellow) indicates the class of gene-set. Node size is proportional to the total number of genes in each set and edge thickness represents the number of overlapping genes between sets. a, Gene-sets enriched for deletions are shown (red) with enrichment significance (FDR q-value) represented as a node color gradient. Groups of functionally related gene-sets are circled and labeled (groups, solid line; sub-groups, dashed line). b, An expanded enrichment map shows the relationship between gene-sets enriched in deletions (panel a) and sets of known ASD/ID genes. Node color hue represents the class of gene-set (i.e. enriched in deletions, red; known disease genes (ie. ASD and/or ID genes), blue; enriched only in disease genes, yellow). Edge color represents the overlap between gene-sets enriched in deletions (green), from disease genes to enriched sets (blue), and between sets enriched in deletions and in disease genes or between disease gene-sets only (orange). The major functional groups are highlighted by filled circles (enriched in deletions, green; enriched in ASD/ID, blue).
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