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

Lookup NU author(s): Dr Rhys ThomasORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2015. 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.

Publication metadata

Author(s): Leu C, Balestrini S, Maher B, Hernandez-Hernandez L, Gormley P, Hamalainen E, Heggeli K, Schoeler N, Novy J, Willis J, Plagnol V, Ellis R, Reavey E, O'Regan M, Pickrell WO, Thomas RH, Chung S-K, Delanty N, McMahon JM, Malone S, Sadleir LG, Berkovic SF, Nashef L, Zuberi SM, Rees MI, Cavalleri GL, Sander JW, Hughes E, Helen Cross J, Scheffer IE, Palotie A, Sisodiya SM

Publication type: Article

Publication status: Published

Journal: EBioMedicine

Year: 2015

Volume: 2

Issue: 9

Pages: 1063-1070

Print publication date: 01/09/2015

Online publication date: 10/07/2015

Acceptance date: 01/07/2015

Date deposited: 07/09/2017

ISSN (electronic): 2352-3964

Publisher: Elsevier B.V.


DOI: 10.1016/j.ebiom.2015.07.005

PubMed id: 26501104


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