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

2015; Elsevier BV; Volume: 2; Issue: 9 Linguagem: Inglês

10.1016/j.ebiom.2015.07.005

2352-3964

Costin Leu, Simona Balestrini, Bridget H. Maher, Laura Hernandez‐Hernandez, Padhraig Gormley, Eija Hämäläinen, Kristin Heggeli, Natasha E. Schoeler, Jan Nový, Joseph Willis, Vincent Plagnol, Rachael Ellis, Eleanor Reavey, Mary O’Regan, William Owen Pickrell, Rhys H. Thomas, Seo‐Kyung Chung, Norman Delanty, Jacinta M. McMahon, Stephen Malone, Lynette G. Sadleir, Samuel F. Berkovic, Lina Nashef, Sameer M. Zuberi, Mark I. Rees, Gianpiero L. Cavalleri, Josemir W. Sander, Elaine Hughes, J. Helen Cross, Ingrid E. Scheffer, Aarno Palotie, Sanjay M. Sisodiya,

Epilepsy research and treatment

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 EBioMedicine 2 (2015) 1063-