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

Publication ,  Journal Article
Heinzen, EL; Depondt, C; Cavalleri, GL; Ruzzo, EK; Walley, NM; Need, AC; Ge, D; He, M; Cirulli, ET; Zhao, Q; Cronin, KD; Gumbs, CE; Hong, LK ...
Published in: Am J Hum Genet
August 10, 2012

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

August 10, 2012

Volume

91

Issue

2

Start / End Page

293 / 302

Location

United States

Related Subject Headings

  • White People
  • Sequence Analysis, DNA
  • Sequence Alignment
  • Molecular Sequence Data
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Predisposition to Disease
  • Exome
 

Citation

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Heinzen, E. L., Depondt, C., Cavalleri, G. L., Ruzzo, E. K., Walley, N. M., Need, A. C., … Goldstein, D. B. (2012). Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am J Hum Genet, 91(2), 293–302. https://doi.org/10.1016/j.ajhg.2012.06.016
Heinzen, Erin L., Chantal Depondt, Gianpiero L. Cavalleri, Elizabeth K. Ruzzo, Nicole M. Walley, Anna C. Need, Dongliang Ge, et al. “Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy.Am J Hum Genet 91, no. 2 (August 10, 2012): 293–302. https://doi.org/10.1016/j.ajhg.2012.06.016.
Heinzen EL, Depondt C, Cavalleri GL, Ruzzo EK, Walley NM, Need AC, et al. Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am J Hum Genet. 2012 Aug 10;91(2):293–302.
Heinzen, Erin L., et al. “Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy.Am J Hum Genet, vol. 91, no. 2, Aug. 2012, pp. 293–302. Pubmed, doi:10.1016/j.ajhg.2012.06.016.
Heinzen EL, Depondt C, Cavalleri GL, Ruzzo EK, Walley NM, Need AC, Ge D, He M, Cirulli ET, Zhao Q, Cronin KD, Gumbs CE, Campbell CR, Hong LK, Maia JM, Shianna KV, McCormack M, Radtke RA, O’Conner GD, Mikati MA, Gallentine WB, Husain AM, Sinha SR, Chinthapalli K, Puranam RS, McNamara JO, Ottman R, Sisodiya SM, Delanty N, Goldstein DB. Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am J Hum Genet. 2012 Aug 10;91(2):293–302.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

August 10, 2012

Volume

91

Issue

2

Start / End Page

293 / 302

Location

United States

Related Subject Headings

  • White People
  • Sequence Analysis, DNA
  • Sequence Alignment
  • Molecular Sequence Data
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Predisposition to Disease
  • Exome