TY - JOUR
T1 - Ultra-Rare Genetic Variation in the Epilepsies
T2 - A Whole-Exome Sequencing Study of 17,606 Individuals
AU - Epi25 Collaborative s.berkovic@unimelb.edu.au bneale@broadinstitute.org
AU - Genomic Psychiatry Cohort GPC Consortium
AU - Feng, Yen Chen Anne
AU - Howrigan, Daniel P.
AU - Abbott, Liam E.
AU - Tashman, Katherine
AU - Cerrato, Felecia
AU - Singh, Tarjinder
AU - Heyne, Henrike
AU - Byrnes, Andrea
AU - Churchhouse, Claire
AU - Watts, Nick
AU - Solomonson, Matthew
AU - Lal, Dennis
AU - Heinzen, Erin L.
AU - Dhindsa, Ryan S.
AU - Stanley, Kate E.
AU - Cavalleri, Gianpiero L.
AU - Hakonarson, H.
AU - Helbig, Ingo
AU - Krause, Roland
AU - May, Patrick
AU - Weckhuysen, S.
AU - Petrovski, Slavé
AU - Kamalakaran, Sitharthan
AU - Sisodiya, Sanjay M.
AU - Cossette, Patrick
AU - Cotsapas, C.
AU - De Jonghe, P.
AU - Dixon-Salazar, T.
AU - Guerrini, R.
AU - Kwan, Patrick
AU - Marson, Anthony G.
AU - Stewart, R.
AU - Depondt, Chantal
AU - Dlugos, Dennis J.
AU - Scheffer, Ingrid E.
AU - Striano, Pasquale
AU - Freyer, Catharine
AU - McKenna, K.
AU - Regan, Brigid M.
AU - Bellows, Susannah T.
AU - Leu, Costin
AU - Bennett, Caitlin A.
AU - Johns, Esther M.C.
AU - Macdonald, Alexandra
AU - Shilling, Hannah
AU - Burgess, Rosemary
AU - Weckhuysen, Dorien
AU - Bahlo, Melanie
AU - O'Brien, Terence J.
AU - Ferraro, Thomas N.
N1 - Funding Information:
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 Discov-EHR 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.
Funding Information:
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 Discov-EHR 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.
Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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 GABAA 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 CACNA1G, 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.
AB - 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 GABAA 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 CACNA1G, 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.
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U2 - 10.1016/j.ajhg.2019.05.020
DO - 10.1016/j.ajhg.2019.05.020
M3 - Article
C2 - 31327507
AN - SCOPUS:85069831549
VL - 105
SP - 267
EP - 282
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -