Abstract
Idiopathic generalized epilepsy (IGE) is a complex disease with high heritability, but little is known about its genetic architecture. Rarecopy-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 IGEphenotype 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.
Highlights
In the past decade, there have been extensive efforts to identify the genetic basis of common, complex human disease
Exome Sequencing After exome sequencing, alignment, and a series of qualitycontrol steps, we isolated 97,242 nonsense, missense, or essential splice-site SNVs that were in transcripts encoding a Human Genome Organization (HUGO)-defined protein-coding gene and that had a control minor allele frequency (MAF) of less than 5% from the variant profiles identified in the 118 Idiopathic generalized epilepsy (IGE) cases and 242 controls
We evaluated 3,349 candidate epilepsysusceptibility variants in a larger cohort of 878 cases and 1,830 controls and did not find any variants with statistically significant associations
Summary
There have been extensive efforts to identify the genetic basis of common, complex human disease. Until recently, this effort has focused primarily on common variants with the use of genome-wide association studies. A number of important gene discoveries have emerged from this work, most of the identified variants have only a small effect on disease risk, of neuropsychiatric diseases.[1] Recently, studies have demonstrated that rare copynumber variants (CNVs) contribute to the risk of developing neurological, psychiatric, and developmental disorders.[2,3,4,5,6,7,8,9,10] These findings implicate specific risk loci in these diseases and support the role of rare variation in the genetic architecture of neuropsychiatric diseases. The optimum NGS study design for identifying causal genetic loci in complex disease will evolve as we expand our knowledge of the underlying genetic architecture, NGS studies evaluating the role of rare variants in complex diseases at this stage include two broadly defined approaches: (1) variant-based assessments for exploring the role of individual variants that have a relatively large effect and that are common enough to be seen in multiple cases and (2) gene-level approaches that seek to identify multiple rare risk alleles within the same genes
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