Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

• Published in: American journal of human genetics Vol. 94; no. 5; pp. 677 - 694
• Main Authors: Pinto, Dalila, Delaby, Elsa, Merico, Daniele, Barbosa, Mafalda, Merikangas, Alison, Klei, Lambertus, Thiruvahindrapuram, Bhooma, Xu, Xiao, Ziman, Robert, Vorstman, Jacob A.S., Thompson, Ann, Regan, Regina, Pilorge, Marion, Pellecchia, Giovanna, Pagnamenta, Alistair T., Oliveira, Bárbara, Magalhaes, Tiago R., Lowe, Jennifer K., Howe, Jennifer L., Gilbert, John, Duketis, Eftichia, Dombroski, Beth A., Cuccaro, Michael, Crawford, Emily L., Correia, Catarina T., Conroy, Judith, Conceição, Inês C., Chiocchetti, Andreas G., Casey, Jillian P., Cai, Guiqing, Cabrol, Christelle, Bacchelli, Elena, Gallinger, Steven, Cotterchio, Michelle, Zwaigenbaum, Lonnie, Wittemeyer, Kerstin, Wing, Kirsty, van Engeland, Herman, Tryfon, Ana, Thomson, Susanne, Rogé, Bernadette, Roberts, Wendy, Poustka, Fritz, Mouga, Susana, Minshew, Nancy, McInnes, L. Alison, McGrew, Susan G., Lord, Catherine, Leboyer, Marion, Le Couteur, Ann S., Kolevzon, Alexander, Jiménez González, Patricia, Jacob, Suma, Holt, Richard, Guter, Stephen, Green, Jonathan, Green, Andrew, Gillberg, Christopher, Duque, Frederico, Delorme, Richard, Dawson, Geraldine, Chaste, Pauline, Café, Cátia, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F., Bernier, Raphael, Baird, Gillian, Bailey, Anthony J., Almeida, Joana, Wijsman, Ellen M., Vieland, Veronica J., Vicente, Astrid M., Schellenberg, Gerard D., Pericak-Vance, Margaret, Paterson, Andrew D., Parr, Jeremy R., Oliveira, Guiomar, Nurnberger, John I., Monaco, Anthony P., Maestrini, Elena, Klauck, Sabine M., Hakonarson, Hakon, Haines, Jonathan L., Geschwind, Daniel H., Freitag, Christine M., Folstein, Susan E., Ennis, Sean, Coon, Hilary, Battaglia, Agatino, Szatmari, Peter, Sutcliffe, James S., Hallmayer, Joachim, Gill, Michael, Cook, Edwin H., Buxbaum, Joseph D., Devlin, Bernie, Gallagher, Louise, Betancur, Catalina, Scherer, Stephen W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2014; Cell Press; Elsevier (Cell Press); Elsevier
• Subjects: Autism; Child; Child Development Disorders, Pervasive - genetics; Chromatin; DNA Copy Number Variations; Female; Gene Regulatory Networks; Genes; Genetics; Humans; Learning disabilities; Life Sciences; Male; Metabolic Networks and Pathways - genetics; Multigene Family; Neurological disorders; Pedigree; Proteins; Psychiatry; Psykiatri; Sequence Deletion; HDAC4; SETD5; gene networks; GDI1; rare CNV; de novo; inherited; pathways; CHD2; Copy Number Variation; autism
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2014.03.018

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10−5) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10−15, ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.