Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects

Rare and large copy number variants (CNVs) around known genomic ‘hotspots’ are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.