Global characterization of copy number variants in epilepsy patients from whole genome sequencing

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs. Using WGS and PopSV, we performed a comprehensive characterization of CNVs in 198 individuals affected with epilepsy and 301 controls. For both large and small variants, we found an enrichment of rare exonic events in epilepsy patients, especially in genes with predicted loss-of-function intolerance. Notably, this genome-wide survey also revealed an enrichment of rare non-coding CNVs near previously known epilepsy genes. This enrichment was strongest for non-coding CNVs located within 100 Kbp of an epilepsy gene and in regions associated with changes in the gene expression, such as expression QTLs or DNase I hypersensitive sites. Finally, we report on 21 potentially damaging events that could be associated with known or new candidate epilepsy genes. Our results suggest that comprehensive sequence-based profiling of CNVs could help explain a larger fraction of epilepsy cases.Author summaryEpilepsy is a common neurological disorder affecting around 3% of the population. In some cases, epilepsy is caused by brain trauma or other brain anomalies but there are often no clear causes. Genetic factors have been associated with epilepsy in the past such as rare genetic variations found by linkage studies as well as common genetic variations found by genome-wide association studies and large copy-number variants. We sequenced the genome of ∼200 epilepsy patients and ∼300 healthy controls and compared the distribution of deletion (loss of a copy) and duplication (additional copy) of genomic regions. Thanks to the sequencing technology and a new method that takes advantage of the large sample size, we could compare the distribution of small copy- number variants between epilepsy patients and controls. Overall, we found that small variants are also associated with epilepsy. Indeed, the genome of epilepsy patients had more exonic copy- number variants, especially when rare or affecting genes with predicted loss-of-function intolerance. Focusing on regions around genes that have been previously associated with epilepsy, we also found more non-coding variants in epilepsy patients, especially deletions or variants in regulatory regions. Finally, we provide a list of 21 regions in which we found likely pathogenic variants.