| Title: |
Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals |
| Authors: |
Epi25 Collaborative; Genomic Psychiat Cohort GPC Consor; Feng, Yen-Chen Anne; Howrigan, Daniel P.; Heyne, Henrike; Linnankivi, Tarja; Lehesjoki, Anna-Elina; Palotie, Aarno; Daly, Mark J.; Neale, Benjamin M. |
| Contributors: |
Institute for Molecular Medicine Finland; Children's Hospital; HUS Children and Adolescents; Department of Medical and Clinical Genetics; University Management; Centre of Excellence in Complex Disease Genetics; Aarno Palotie / Principal Investigator; Genomics of Neurological and Neuropsychiatric Disorders |
| Publisher Information: |
Cell Press |
| Publication Year: |
2020 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
DE-NOVO MUTATIONS; EPILEPTIC SEIZURES; COMMON EPILEPSIES; VARIANTS; PROTEIN; METAANALYSIS; GENOME; GAMMA-2-SUBUNIT; SUSCEPTIBILITY; EPIDEMIOLOGY; Biomedicine; Genetics; developmental biology; physiology |
| Description: |
Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA(A) receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNAIG, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
We gratefully thank the Epi25 principal investigators, local staff from individual cohorts, and all of the individuals with epilepsy who participated in the study for making possible this global collaboration and resource to advance epilepsy genetics research. 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 research activities at the Broad Institute were supported by NHGRI grant UM1 HG008895. The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088-02. 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), with D.H.L. and S.F.B. as the principal investigators. Additional funding sources and acknowledgment of individual case and control cohorts were listed in the Supplemental Data. We thank the Stanley Center for Psychiatric Research at the Broad Institute for supporting sequencing effort and control sample aggregation. The authors would like to thank the DiscovEHR collaboration of Geisinger Health System and Regeneron for providing exome variant data for comparison. We also thank Sali Farhan, Kyle Satterstrom, and Chai-Yen Chen for helpful discussions, Nick Watts and Matthew Solomonson for browser development, and the Hail team for analysis support.; https://hdl.handle.net/10138/312995; 000478022200004 |
| Availability: |
https://hdl.handle.net/10138/312995 |
| Rights: |
info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.D56C4A71 |
| Database: |
BASE |