Open AccessGlobal characterization of copy number variants in epilepsy patients from whole genome sequencing
Author(s) -
Jean Monlong,
Simon L. Girard,
Caroline Meloche,
Maxime Cadieux-Dion,
Danielle Andrade,
Ron G. Lafrenière,
Micheline Gravel,
Dan Spiegelman,
Alexandre DionneLaporte,
Cyrus Boelman,
Fadi F. Hamdan,
Jacques L. Michaud,
Guy A. Rouleau,
Berge A. Minassian,
Guillaume Bourque,
Patrick Cossette
Publication year - 2018
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1007285
Subject(s) - copy number variation , epilepsy , biology , genetics , genome , gene , coding region , whole genome sequencing , computational biology , neuroscience
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.