Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy.

Détails

Ressource 1Télécharger: BIB_8B742A0505B8.P001.pdf (664.04 [Ko])
Etat: Serval
Version: Final published version
ID Serval
serval:BIB_8B742A0505B8
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy.
Périodique
Ebiomedicine
Auteur(s)
Leu C., Balestrini S., Maher B., Hernández-Hernández L., Gormley P., Hämäläinen E., Heggeli K., Schoeler N., Novy J., Willis J., Plagnol V., Ellis R., Reavey E., O'Regan M., Pickrell W.O., Thomas R.H., Chung S.K., Delanty N., McMahon J.M., Malone S., Sadleir L.G., Berkovic S.F., Nashef L., Zuberi S.M., Rees M.I., Cavalleri G.L., Sander J.W., Hughes E., Helen Cross J., Scheffer I.E., Palotie A., Sisodiya S.M.
ISSN
2352-3964 (Electronic)
ISSN-L
2352-3964
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
2
Numéro
9
Pages
1063-1070
Langue
anglais
Résumé
Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10(- 3)) and non-epilepsy disease controls (P = 1.2 × 10(- 3)). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP.
Pubmed
Open Access
Oui
Création de la notice
21/06/2016 20:25
Dernière modification de la notice
08/05/2019 21:42
Données d'usage