Genome-wide analysis identifies a role for common copy number variants in specific language impairment

Nuala H Simpson, Fabiola Ceroni, Rose H Reader, Laura E Covill, Julian C Knight, Elizabeth R Hennessy, Patrick F Bolton, Gina Conti-Ramsden, Anne O'Hare, Gillian Baird, Simon E Fisher, Dianne F Newbury, The SLI Consortium

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An exploratory genome-wide copy number variant (CNV) study was performed in 127 independent cases with specific language impairment (SLI), their first-degree relatives (385 individuals) and 269 population controls. Language-impaired cases showed an increased CNV burden in terms of the average number of events (11.28 vs 10.01, empirical P=0.003), the total length of CNVs (717 vs 513 Kb, empirical P=0.0001), the average CNV size (63.75 vs 51.6 Kb, empirical P=0.0005) and the number of genes spanned (14.29 vs 10.34, empirical P=0.0007) when compared with population controls, suggesting that CNVs may contribute to SLI risk. A similar trend was observed in first-degree relatives regardless of affection status. The increased burden found in our study was not driven by large or de novo events, which have been described as causative in other neurodevelopmental disorders. Nevertheless, de novo CNVs might be important on a case-by-case basis, as indicated by identification of events affecting relevant genes, such as ACTR2 and CSNK1A1, and small events within known micro-deletion/-duplication syndrome regions, such as chr8p23.1. Pathway analysis of the genes present within the CNVs of the independent cases identified significant overrepresentation of acetylcholine binding, cyclic-nucleotide phosphodiesterase activity and MHC proteins as compared with controls. Taken together, our data suggest that the majority of the risk conferred by CNVs in SLI is via common, inherited events within a 'common disorder-common variant' model. Therefore the risk conferred by CNVs will depend upon the combination of events inherited (both CNVs and SNPs), the genetic background of the individual and the environmental factors.European Journal of Human Genetics advance online publication, 14 January 2015; doi:10.1038/ejhg.2014.296.

Original languageEnglish
Pages (from-to)1370-1377
Number of pages8
JournalEJHG : European journal of human genetics : the official journal of the European Society of Human Genetics.
Issue number10
Early online date14 Jan 2015
Publication statusPublished - 2015

Bibliographical note

We would like to thank all the families, professionals and individuals who participated in this research. DNF is an MRC Career Development Fellow and a Junior Research Fellow at St John’s College, University of Oxford. The work of the Newbury lab is funded by the Medical Research Council (G1000569/1 and MR/J003719/1). The collection of the SLIC samples was supported by the Wellcome Trust (060774 and 076566). The genotyping of samples was funded by the Max Planck Society. Recruitment of controls was supported by the Wellcome Trust (074318 and 088891), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013; 281824) and the National Institute for Health Research (NIHR), Oxford Biomedical Research Centre. FC was supported by the PhD Programme in Molecular and Cellular Biology of the University of Bologna. PFB is supported by a National Institute of Health Research (UK) Senior Investigator award and the Biomedical Research Centre in Mental Health at the South London and Maudsley NHS Trust Hospital, London, UK. The work of the Wellcome Trust Centre in Oxford is supported by the Wellcome Trust (090532/Z/09/Z).


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