Abstracts

Rationale: Rare copy number variants (CNVs) are strongly implicated in the etiology of epilepsy. We previously published an association study of CNVs with different types of epilepsy in ~10k European epilepsy cases and ~6k ancestry-matched controls (Niestroj et al., 2019, Brain). We observed large differences in the CNV burden across epilepsy types and different CNV categories. We found that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy (GGE), with a 34-fold risk for developing GGE. However, similar to most previous epilepsy genetics studies, we focused only on individuals with European ancestry. The distribution of CNVs that confer risk towards epilepsy and their effect sizes are not well established in non-European populations.

Methods: Using genome-wide genotyping data generated with the Illumina Global Screening Array-24 v1.0, we reanalyzed the current cohort of the Epi25 Consortium together with new genetic data, totaling 21,706 individuals with epilepsy and 12,426 ancestry-matched controls for the burden of rare CNVs.

Results: We identified 25,172 European- (EUR), 4,087 African- (AFR), and 1,824 Asian-ancestry (ASN) individuals in our study available for CNV burden analyses after quality control. Across all ancestries, we identified 305 CNV carriers of seven established epilepsy-associated CNV hotspots in 19,079 individuals with epilepsy and 70 carriers among 12,004 controls. Among all tested epilepsy subsyndromes and in line with previous evidence, we observed the highest CNV burden in individuals with GGE. The two most common recurrent CNVs, deletions at 15q11.2 and 16p13.11, known to be associated with GGE in European individuals, were also enriched in African and Asian individuals with GGE, with effect sizes similar to those in European individuals (e.g., 15q11.2: P_EUR=6.89x10^-5, OR_EUR=2.44 vs. P_AFR=9.49x10^-3, OR_AFR=3.96; or 16p13.11: P_EUR=9.26x10^-12, OR_EUR=25.9 vs. P_ASN=6.58x10^-3, OR_ASN=26.4). At the time of the conference, we will present additional analyses of different classes of CNVs and genome-wide CNV breakpoint association analyses that explore the similarities and possible differences between CNV architectures of European, African, and Asian ancestries.

Conclusions: Our study represents the largest and the first transethnic evaluation of the CNV burden in epilepsy. Our preliminary results indicate that established recurrent CNVs have similar effect sizes in different ethnicities. As CNVs are part of clinical genetic testing, our results will likely help alleviate health care disparities.

Funding: Please list any funding that was received in support of this abstract.: This work is part of the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, are supported by NHGRI grant UM1 HG008895 (PIs: Eric Lander, Stacey Gabriel, Mark Daly, Sekar Kathiresan). Supplemental Epi25 phenotyping was supported by “Epi25 Clinical Phenotyping R03” National Institutes of Health (1R03NS108145-01) (PIs: Daniel Lowenstein, Samuel Berkovic).