[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Aug 2012 · The American Journal of Human Genetics
[Show abstract][Hide abstract] ABSTRACT: F8 variants. This image shows the positions of the F8 variants that were observed in our dataset. Image modified from Ge et al. and Hubbard et al.
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[Show abstract][Hide abstract] ABSTRACT: Position of protein truncating variants within coding sequences. These graphs show the relative locations of stop-gain SNVs (A) and frameshift indels (B) within protein-coding sequences. A relative location near 0.1 (left side of x-axis) indicates that the variant is near the N-terminus, while a location near 1.0 (right side of x-axis) indicates that the variant is near the C-terminus. The y-axis is the absolute count of variants. Figures include both homozygous and heterozygous variants from across all 20 genomes.
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[Show abstract][Hide abstract] ABSTRACT: Location of identified variants observed across all 20 genomes. These graphs show the functional distribution of SNVs (A) and indels (B) based on their location in relation to annotated transcripts.
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[Show abstract][Hide abstract] ABSTRACT: We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.