Rare copy number variants are an important cause of epileptic encephalopathies.
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ABSTRACT:
SUBMITTER: Mefford HC
PROVIDER: S-EPMC3245646 | biostudies-literature | 2011 Dec
REPOSITORIES: biostudies-literature
Publications
Rare copy number variants are an important cause of epileptic encephalopathies.
Mefford Heather C HC Yendle Simone C SC Hsu Cynthia C Cook Joseph J Geraghty Eileen E McMahon Jacinta M JM Eeg-Olofsson Orvar O Sadleir Lynette G LG Gill Deepak D Ben-Zeev Bruria B Lerman-Sagie Tally T Mackay Mark M Freeman Jeremy L JL Andermann Eva E Pelakanos James T JT Andrews Ian I Wallace Geoffrey G Eichler Evan E EE Berkovic Samuel F SF Scheffer Ingrid E IE
Annals of neurology 20111201 6
<h4>Objective</h4>Rare copy number variants (CNVs)--deletions and duplications--have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure group of epilepsies, has not been performed.<h4>Methods</h4>We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CN ...[more]
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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.
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