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Describing the genetic architecture of epilepsy through heritability analysis

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Title: Describing the genetic architecture of epilepsy through heritability analysis
Authors: Speed, D
O'Brien, TJ
Palotie, A
Shkura, K
Marson, AG
Balding, DJ
Johnson, MR
Item Type: Journal Article
Abstract: Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy.
Issue Date: 1-Oct-2014
Date of Acceptance: 14-Jun-2014
URI: http://hdl.handle.net/10044/1/61428
DOI: https://dx.doi.org/10.1093/brain/awu206
ISSN: 1460-2156
Publisher: Oxford University Press (OUP)
Start Page: 2680
End Page: 2689
Journal / Book Title: Brain
Volume: 137
Issue: 10
Copyright Statement: © 2014 The Author. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
epilepsy
association studies
heritability analysis
complex trait prediction
GENOME-WIDE ASSOCIATION
IDIOPATHIC GENERALIZED EPILEPSY
16P13.11 PREDISPOSE
SEIZURES
DISEASES
ILAE
CLASSIFICATION
SUSCEPTIBILITY
MICRODELETIONS
RISK
Age of Onset
Algorithms
Area Under Curve
Asian Continental Ancestry Group
Epilepsy
European Continental Ancestry Group
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Genotyping Techniques
Humans
Models, Statistical
Polymorphism, Single Nucleotide
Population
Quantitative Trait, Heritable
ROC Curve
Seizures
11 Medical And Health Sciences
17 Psychology And Cognitive Sciences
Neurology & Neurosurgery
Publication Status: Published
Online Publication Date: 2014-07-25
Appears in Collections:Department of Medicine (up to 2019)