Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Pinto, D. et al. (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. American Journal of Human Genetics, 94(5), pp. 677-694. (doi: 10.1016/j.ajhg.2014.03.018) (PMID:24768552) (PMCID:PMC4067558)

Abstract

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.

• Item Type: Articles
• Additional Information: The authors thank the main funders of the Autism Genome Project: Autism Speaks (USA), the Health Research Board (Ireland; AUT/2006/1, AUT/2006/2, PD/2006/48), the Medical Research Council (UK), the Hilibrand Foundation (USA), Genome Canada, the Ontario Genomics Institute, and the Canadian Institutes of Health Research (CIHR).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gillberg, Professor Christopher
• Authors: Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., Vorstman, J. A.S., Thompson, A., Regan, R., Pilorge, M., Pellecchia, G., Pagnamenta, A. T., Oliveira, B., Marshall, C. R., Magalhaes, T. R., Lowe, J. K., Howe, J. L., Griswold, A. J., Gilbert, J., Duketis, E., Dombroski, B. A., De Jonge, M. V., Cuccaro, M., Crawford, E. L., Correia, C. T., Conroy, J., Conceição, I. C., Chiocchetti, A. G., Casey, J. P., Cai, G., Cabrol, C., Bolshakova, N., Bacchelli, E., Anney, R., Gallinger, S., Cotterchio, M., Casey, G., Zwaigenbaum, L., Wittemeyer, K., Wing, K., Wallace, S., van Engeland, H., Tryfon, A., Thomson, S., Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McInnes, L. A., McGrew, S. G., Lord, C., Leboyer, M., Le Couteur, A. S., Kolevzon, A., Jiménez González, P., Jacob, S., Holt, R., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B. A., Duque, F., Delorme, R., Dawson, G., Chaste, P., Café, C., Brennan, S., Bourgeron, T., Bolton, P. F., Bölte, S., Bernier, R., Baird, G., Bailey, A. J., Anagnostou, E., Almeida, J., Wijsman, E. M., Vieland, V. J., Vicente, A. M., Schellenberg, G. D., Pericak-Vance, M., Paterson, A. D., Parr, J. R., Oliveira, G., Nurnberger, J. I., Monaco, A. P., Maestrini, E., Klauck, S. M., Hakonarson, H., Haines, J. L., Geschwind, D. H., Freitag, C. M., Folstein, S. E., Ennis, S., Coon, H., Battaglia, A., Szatmari, P., Sutcliffe, J. S., Hallmayer, J., Gill, M., Cook, E. H., Buxbaum, J. D., Devlin, B., Gallagher, L., Betancur, C., and Scherer, S. W.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: American Journal of Human Genetics
• Publisher: Elsevier (Cell Press)
• ISSN: 0002-9297
• ISSN (Online): 1537-6605
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in American Journal of Human Genetics 94: 677-694
• Publisher Policy: Reproduced under a creative commons licence