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

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 WO, Thomas RH, Chung SK, 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 - EBioMedicine (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.

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.

No MeSH data available.


Related in: MedlinePlus

Individual-level quality control flowchart for the SUDEP, epilepsy control, and non-epilepsy disease control samples used in this study. Abbreviations: WES, whole-exome sequencing; SUDEP, sudden unexpected death in epilepsy.
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f0005: Individual-level quality control flowchart for the SUDEP, epilepsy control, and non-epilepsy disease control samples used in this study. Abbreviations: WES, whole-exome sequencing; SUDEP, sudden unexpected death in epilepsy.

Mentions: We used whole-exome sequencing (WES) data from 18 people with epilepsy who died of SUDEP and two control cohorts: a group of 87 living people with epilepsy, which we termed ‘epilepsy controls’, and 1479 non-epilepsy ‘disease control’ samples. To ensure data homogeneity, a joint calling strategy, and stringent variant and individual-level quality control (QC) were applied for all WES datasets (Fig. 1 and Supplementary Methods 5–8). Only individuals of white European ancestry were included in subsequent analyses (Supplementary Method 6.2 and Supplementary Fig. 1). We tested the genome-wide burden of rare (or novel) deleterious variants in the SUDEP cohort against both control cohorts separately. Supported by the findings of the genome-wide burden analysis, we sought to identify candidate genes for SUDEP using gene-based association analyses. The study analytic design is outlined in the Supplementary Fig. 2.


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

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 WO, Thomas RH, Chung SK, 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 - EBioMedicine (2015)

Individual-level quality control flowchart for the SUDEP, epilepsy control, and non-epilepsy disease control samples used in this study. Abbreviations: WES, whole-exome sequencing; SUDEP, sudden unexpected death in epilepsy.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588398&req=5

f0005: Individual-level quality control flowchart for the SUDEP, epilepsy control, and non-epilepsy disease control samples used in this study. Abbreviations: WES, whole-exome sequencing; SUDEP, sudden unexpected death in epilepsy.
Mentions: We used whole-exome sequencing (WES) data from 18 people with epilepsy who died of SUDEP and two control cohorts: a group of 87 living people with epilepsy, which we termed ‘epilepsy controls’, and 1479 non-epilepsy ‘disease control’ samples. To ensure data homogeneity, a joint calling strategy, and stringent variant and individual-level quality control (QC) were applied for all WES datasets (Fig. 1 and Supplementary Methods 5–8). Only individuals of white European ancestry were included in subsequent analyses (Supplementary Method 6.2 and Supplementary Fig. 1). We tested the genome-wide burden of rare (or novel) deleterious variants in the SUDEP cohort against both control cohorts separately. Supported by the findings of the genome-wide burden analysis, we sought to identify candidate genes for SUDEP using gene-based association analyses. The study analytic design is outlined in the Supplementary Fig. 2.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.

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.

No MeSH data available.


Related in: MedlinePlus