期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 91, 期 2, 页码 293-302出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2012.06.016
关键词
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资金
- National Institute of Neurological Disorders and Stroke [RC2NS070344]
- National Institute of Mental Health [RC2MH089915]
- National Institute of Allergy and Infectious Diseases [UO1AIO67854, 1RC2NS070342]
- Ellison Medical Foundation
- National Institute on Aging [P30 AG028377]
- Wellcome Trust [084730]
- National Institute for Health Research [08-08-SCC]
- Fonds National de la Recherche Scientifique
- Fondation Erasme
- Universite Libre de Bruxelles
- Fondation Erasme, Universite Libre de Bruxelles, Brainwave-The Irish Epilepsy Association/the Medical Research Charities Group of Ireland/Health Research Board [2009/001]
- Programme for Human Genomics
- Programme for Research in Third Level Institutions (PRTLI3)
- Irish Higher Education Authority
- Health Research Board of Ireland's Translational Research Scholars award
Idiopathic generalized epilepsy (ICE) 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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