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

Abstract

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.eCollection. Cited Medium: Internet. NLM ISO Abbr: EBioMedicine. PubMed Central ID: PMC4588398. Linked References: Epilepsia. 2008 Feb;49(2):360-5. (PMID: 18251839); Neuron. 2014 Sep 3;83(5):1159-71. (PMID: 25189211); Am J Forensic Med Pathol. 2005 Jun;26(2):99-105. (PMID: 15897710); Am J Hum Genet. 2014 May 1;94(5):760-9. (PMID: 24791901); Nat Neurosci. 2007 Dec;10(12):1554-8. (PMID: 17982453); PLoS Genet. 2012 Feb;8(2):e1002496. (PMID: 22319458); PLoS Genet. 2014 May 01;10(5):e1004314. (PMID: 24786987); Epilepsia. 2014 Oct;55(10):1479-85. (PMID: 24903551); Ann Neurol. 2010 Dec;68(6):787-96. (PMID: 20882604); Nat Commun. 2010 Nov 30;1:131. (PMID: 21119644); J Neurol Neurosurg Psychiatry. 1995 Apr;58(4):462-4. (PMID: 7738555); Epilepsia. 2010 Apr;51(4):690-3. (PMID: 19780791); Neurology. 2014 Sep 9;83(11):1018-21. (PMID: 25085640); BMC Res Notes. 2014 Oct 22;7:747. (PMID: 25339461); Neurology. 2001 Feb 27;56(4):519-25. (PMID: 11222798); Epilepsia. 2013 Sep;54(9):e127-30. (PMID: 23758665); Neurology. 2015 Feb 17;84(7):703-9. (PMID: 25609764); Seizure. 2007 Mar;16(2):153-9. (PMID: 17178458); Epilepsia. 2011 Jun;52(6):1150-9. (PMID: 21671925); Bioinformatics. 2015 May 15;31(10):1536-43. (PMID: 25583119); PLoS Genet. 2011 Mar;7(3):e1001322. (PMID: 21408211); J Neurol Neurosurg Psychiatry. 2010 Jul;81(7):716-8. (PMID: 20478848); Epilepsia. 2010 Apr;51(4):676-85. (PMID: 20196795); Epilepsia. 2012 Feb;53(2):253-7. (PMID: 22192074); Epilepsia. 2013 May;54 Suppl 2:23-8. (PMID: 23646967); Nat Protoc. 2014 May;9(5):1192-212. (PMID: 24762786); Curr Neurol Neurosci Rep. 2014 Dec;14(12):502. (PMID: 25300243); Hum Mol Genet. 2015 Jan 15;24(2):506-15. (PMID: 25227913); Epilepsia. 2014 Feb;55(2):e6-12. (PMID: 24372310); Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276); Epilepsia. 2011 Jun;52(6):1144-9. (PMID: 21480880); Am J Hum Genet. 2007 Sep;81(3):559-75. (PMID: 17701901); Nat Rev Neurol. 2014 May;10(5):271-82. (PMID: 24752120); Nat Genet. 2012 May 29;44(6):623-30. (PMID: 22641211); Nature. 2014 Feb 13;506(7487):185-90. (PMID: 24463508); Science. 2004 Aug 6;305(5685):869-72. (PMID: 15297675); Epilepsy Behav. 2013 Jul;28(1):78-82. (PMID: 23666465); Epilepsia. 2012 Feb;53(2):227-33. (PMID: 22191982); Sci Transl Med. 2009 Oct 14;1(2):2ra6. (PMID: 20368164). Linking ISSN: 23523964. Subset: MEDLINE; Grant Information: 104033 United Kingdom Wellcome Trust Date of Electronic Publication: 2015 Jul 10. ; Original Imprints: Publication: [Amsterdam] : Elsevier B.V., [2014]-Note: Original DateCompleted: 20151027. <br />