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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

Violin plots of the burden score and variant number per individual. Plotted are the per-individual burden scores (A) and the number of variants per individual (B) of each test group. A violin plot is a box plot with the width of the box proportional to the estimated density of the observed data (proportion of cases with given ordinate value). The maximum density of the group-specific data distribution is indicated by the largest width of the violins. The density trace is plotted symmetrically to the left and the right of the box plot for better visualization. All violins have the same fixed maximum width. The white dot is the median, the thick black vertical bar represents the interquartile range (IQR), and the thin black vertical bar represents 95% confidence intervals.
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f0010: Violin plots of the burden score and variant number per individual. Plotted are the per-individual burden scores (A) and the number of variants per individual (B) of each test group. A violin plot is a box plot with the width of the box proportional to the estimated density of the observed data (proportion of cases with given ordinate value). The maximum density of the group-specific data distribution is indicated by the largest width of the violins. The density trace is plotted symmetrically to the left and the right of the box plot for better visualization. All violins have the same fixed maximum width. The white dot is the median, the thick black vertical bar represents the interquartile range (IQR), and the thin black vertical bar represents 95% confidence intervals.

Mentions: We observed a significantly increased genome-wide burden score 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) (Table 2; Fig. 2, Supplementary Table 6). The number of variants per individual showed suggestive over-representation against the epilepsy controls (P = 0.022), and significant over-representation against disease controls (P = 4.1 × 10− 3) (Table 2, Fig. 2). Although there was also a significant difference in the number of variants between the two control cohorts (P = 6.1 × 10− 3), the genome-wide burden score did not differ. This genome-wide burden suggests an extensive polygenic contribution to SUDEP causation.


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)

Violin plots of the burden score and variant number per individual. Plotted are the per-individual burden scores (A) and the number of variants per individual (B) of each test group. A violin plot is a box plot with the width of the box proportional to the estimated density of the observed data (proportion of cases with given ordinate value). The maximum density of the group-specific data distribution is indicated by the largest width of the violins. The density trace is plotted symmetrically to the left and the right of the box plot for better visualization. All violins have the same fixed maximum width. The white dot is the median, the thick black vertical bar represents the interquartile range (IQR), and the thin black vertical bar represents 95% confidence intervals.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

f0010: Violin plots of the burden score and variant number per individual. Plotted are the per-individual burden scores (A) and the number of variants per individual (B) of each test group. A violin plot is a box plot with the width of the box proportional to the estimated density of the observed data (proportion of cases with given ordinate value). The maximum density of the group-specific data distribution is indicated by the largest width of the violins. The density trace is plotted symmetrically to the left and the right of the box plot for better visualization. All violins have the same fixed maximum width. The white dot is the median, the thick black vertical bar represents the interquartile range (IQR), and the thin black vertical bar represents 95% confidence intervals.
Mentions: We observed a significantly increased genome-wide burden score 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) (Table 2; Fig. 2, Supplementary Table 6). The number of variants per individual showed suggestive over-representation against the epilepsy controls (P = 0.022), and significant over-representation against disease controls (P = 4.1 × 10− 3) (Table 2, Fig. 2). Although there was also a significant difference in the number of variants between the two control cohorts (P = 6.1 × 10− 3), the genome-wide burden score did not differ. This genome-wide burden suggests an extensive polygenic contribution to SUDEP causation.

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