Dataset Information

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.

SUBMITTER: Simpson NH

PROVIDER: S-EPMC4592089 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Simpson Nuala H NH Ceroni Fabiola F Reader Rose H RH Covill Laura E LE Knight Julian C JC Hennessy Elizabeth R ER Bolton Patrick F PF Conti-Ramsden Gina G O'Hare Anne A Baird Gillian G Fisher Simon E SE Newbury Dianne F DF

European journal of human genetics : EJHG 20150114 10

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 spanne ...[more]

PMID: 25585696

Similar Datasets

Project description:BackgroundCopy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described.MethodsAssessing four modes of CNV action, we performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 60 curated ICD-10 based clinical diagnoses in 331,522 unrelated white British UK Biobank (UKBB) participants with replication in the Estonian Biobank.ResultsWe identified 73 signals involving 40 diseases, all of which indicating that CNVs increased disease risk and caused earlier onset. We estimated that 16% of these associations are indirect, acting by increasing body mass index (BMI). Signals mapped to 45 unique, non-overlapping regions, nine of which being linked to known GDs. Number and identity of genes affected by CNVs modulated their pathogenicity, with many associations being supported by colocalization with both common and rare single-nucleotide variant association signals. Dissection of association signals provided insights into the epidemiology of known gene-disease pairs (e.g., deletions in BRCA1 and LDLR increased risk for ovarian cancer and ischemic heart disease, respectively), clarified dosage mechanisms of action (e.g., both increased and decreased dosage of 17q12 impacted renal health), and identified putative causal genes (e.g., ABCC6 for kidney stones). Characterization of the pleiotropic pathological consequences of recurrent CNVs at 15q13, 16p13.11, 16p12.2, and 22q11.2 in adulthood indicated variable expressivity of these regions and the involvement of multiple genes. Finally, we show that while the total burden of rare CNVs-and especially deletions-strongly associated with disease risk, it only accounted for ~ 0.02% of the UKBB disease burden. These associations are mainly driven by CNVs at known GD CNV regions, whose pleiotropic effect on common diseases was broader than anticipated by our CNV-GWAS.ConclusionsOur results shed light on the prominent role of rare CNVs in determining common disease susceptibility within the general population and provide actionable insights for anticipating later-onset comorbidities in carriers of recurrent CNVs.

Project description:Reading and language skills have overlapping genetic bases, most of which are still unknown. Part of the missing heritability may be caused by copy number variants (CNVs).In a dataset of children recruited for a history of reading disability (RD, also known as dyslexia) or attention deficit hyperactivity disorder (ADHD) and their siblings, we investigated the effects of CNVs on reading and language performance. First, we called CNVs with PennCNV using signal intensity data from Illumina OmniExpress arrays (~723,000 probes). Then, we computed the correlation between measures of CNV genomic burden and the first principal component (PC) score derived from several continuous reading and language traits, both before and after adjustment for performance IQ. Finally, we screened the genome, probe-by-probe, for association with the PC scores, through two complementary analyses: we tested a binary CNV state assigned for the location of each probe (i.e., CNV+ or CNV-), and we analyzed continuous probe intensity data using FamCNV.No significant correlation was found between measures of CNV burden and PC scores, and no genome-wide significant associations were detected in probe-by-probe screening. Nominally significant associations were detected (p~10(-2)-10(-3)) within CNTN4 (contactin 4) and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules with a likely role in neuronal development, and they have been previously implicated in autism and other neurodevelopmental disorders. A further, targeted assessment of candidate CNV regions revealed associations with the PC score (p~0.026-0.045) within CHRNA7 (cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated ion channel and has also been implicated in neurodevelopmental conditions and language impairment. FamCNV analysis detected a region of association (p~10(-2)-10(-4)) within a frequent deletion ~6 kb downstream of ZNF737 (zinc finger protein 737, uncharacterized protein), which was also observed in the association analysis using CNV calls.These data suggest that CNVs do not underlie a substantial proportion of variance in reading and language skills. Analysis of additional, larger datasets is warranted to further assess the potential effects that we found and to increase the power to detect CNV effects on reading and language.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets