Document Detail

Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy.
MedLine Citation:
PMID:  22863189     Owner:  NLM     Status:  MEDLINE    
Idiopathic generalized epilepsy (IGE) is a complex disease with high heritability, but little is known about its genetic architecture. Rare copy-number variants have been found to explain nearly 3% of individuals with IGE; however, it remains unclear whether variants with moderate effect size and frequencies below what are reliably detected with genome-wide association studies contribute significantly to disease risk. In this study, we compare the exome sequences of 118 individuals with IGE and 242 controls of European ancestry by using next-generation sequencing. The exome-sequenced epilepsy cases include study subjects with two forms of IGE, including juvenile myoclonic epilepsy (n = 93) and absence epilepsy (n = 25). However, our discovery strategy did not assume common genetic control between the subtypes of IGE considered. In the sequence data, as expected, no variants were significantly associated with the IGE phenotype or more specific IGE diagnoses. We then selected 3,897 candidate epilepsy-susceptibility variants from the sequence data and genotyped them in a larger set of 878 individuals with IGE and 1,830 controls. Again, no variant achieved statistical significance. However, 1,935 variants were observed exclusively in cases either as heterozygous or homozygous genotypes. It is likely that this set of variants includes real risk factors. The lack of significant association evidence of single variants with disease in this two-stage approach emphasizes the high genetic heterogeneity of epilepsy disorders, suggests that the impact of any individual single-nucleotide variant in this disease is small, and indicates that gene-based approaches might be more successful for future sequencing studies of epilepsy predisposition.
Erin L Heinzen; Chantal Depondt; Gianpiero L Cavalleri; Elizabeth K Ruzzo; Nicole M Walley; Anna C Need; Dongliang Ge; Min He; Elizabeth T Cirulli; Qian Zhao; Kenneth D Cronin; Curtis E Gumbs; C Ryan Campbell; Linda K Hong; Jessica M Maia; Kevin V Shianna; Mark McCormack; Rodney A Radtke; Gerard D O'Conner; Mohamad A Mikati; William B Gallentine; Aatif M Husain; Saurabh R Sinha; Krishna Chinthapalli; Ram S Puranam; James O McNamara; Ruth Ottman; Sanjay M Sisodiya; Norman Delanty; David B Goldstein
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-02
Journal Detail:
Title:  American journal of human genetics     Volume:  91     ISSN:  1537-6605     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-13     Completed Date:  2012-10-22     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  293-302     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708, USA.
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MeSH Terms
Base Sequence
Epilepsy, Generalized / genetics*
European Continental Ancestry Group / genetics
Exome / genetics*
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Molecular Sequence Data
Sequence Alignment
Sequence Analysis, DNA
Grant Support
084730//Wellcome Trust; 1RC2NS070342/NS/NINDS NIH HHS; RC2MH089915/MH/NIMH NIH HHS; RC2NS070344/NS/NINDS NIH HHS; UO1AIO67854//PHS HHS

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