title: Genome-wide analysis identifies a role for common copy number variants in specific language impairment.
abstract: 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Nuala H
authors.initials: NH
authors.lastname: Simpson
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Ceroni
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Rose H
authors.initials: RH
authors.lastname: Reader
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Covill
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
authors.affiliation: University Child Health and DMDE, University of Aberdeen, Aberdeen, UK.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hennessy
authors.affiliation: Departments of Child and Adolescent Psychiatry, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Bolton
authors.affiliation: School of Psychological Sciences, University of Manchester, Manchester, UK.
authors.forename: Gina
authors.initials: G
authors.lastname: Conti-Ramsden
authors.affiliation: Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Hare
authors.affiliation: Children's Neurosciences Department, Evelina Children's Hospital and King's Health Partners, London, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Baird
authors.affiliation: Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|St John's College, University of Oxford, Oxford, UK.
authors.forename: Dianne F
authors.initials: DF
authors.lastname: Newbury
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007802:Language; D007806:Language Disorders / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics