TY - JOUR
T1 - Ultra-Rare Genetic Variation in the Epilepsies
T2 - A Whole-Exome Sequencing Study of 17,606 Individuals
AU - Epi25 Collaborative [email protected] [email protected]
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 - Buono, Russell J.
AU - Ferraro, Thomas N.
N1 - 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
SN - 0002-9297
VL - 105
SP - 267
EP - 282
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -