Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy

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. MikatiWilliam 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

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)293-302
Number of pages10
JournalAmerican journal of human genetics
Issue number2
StatePublished - Aug 10 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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