Journal article

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Joshua E Motelow, Gundula Povysil, Ryan S Dhindsa, Kate E Stanley, Andrew S Allen, Yen-Chen Anne Feng, Daniel P Howrigan, Liam E Abbott, Katherine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M Neale Show all



Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rar..

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Awarded by National Institutes of Health

Awarded by NHGRI

Funding Acknowledgements

We thank the Epi25 principal investigators, local staff overseeing individual cohorts, and all of the individuals with epilepsy and their families who participated in Epi25 for their commitment to this international collaboration. J.E.M. is supported by the National Institutes of Health (TL1TR001875). 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, and Sekar Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A supplemental grant for Epi25 phenotyping was supported by ``Epi25 Clinical Phenotyping R03,'' National Institutes of Health (1R03NS108145-01); D.H.L. and S.F.B. were the principal investigators. We also thank the Stanley Center for Psychiatric Research at the Broad Institute for supporting the genomic data generation. Additional funding sources and acknowledgment of individual cohorts are listed in the supplemental information.