Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Abstract

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Opportunities and Challenges for Genome Sequencing in the Clinic

“…Several major genome-wide association studies are now underway in epilepsy, but few findings have emerged from these studies so far. In a large GWAS involving over 3000 patients and 4000 controls, we observed only a marginal contribution of common SNPs in conferring risk broadly amongsporadic focal epilepsies (Kasperaviciute et al, 2010), a finding similar to other neuropsychiatric disorders such as schizophrenia, autism, and bipolar disorder (Carroll & Owen, 2009;Purcell et al, 2009). A more recent effort in patients of Chinese descent promoted variation in CAMSAP1L1 as a potential risk factor for epilepsy, although independent replication is required (Guo et al, 2012).…”

“…However, the gene identifications in Mendelian epilepsy syndromes apply to an extremely small proportion of affected individuals. 1989 1991 1993 1995 1999 1997 2001 2003 2007 2005 2009 First epilepsy gene (Steinlein et al, 1995) Candidate gene association studies in sporadic epilepsy First epilepsy GWAS (Kasperaviciute et al, 2010) …”

The genetic variability and commonality of neurodevelopmental disease

“…Despite high heritability estimates for bipolar, epilepsy, schizophrenia, autism, and ID ranging from 73% to more than 90%, relatively few common single nucleotide polymorphisms (SNPs) have been convincingly associated with these diseases [Marshall et al, 2008;Stefansson et al, 2008;Wang et al, 2009;Kasperaviciūte et al, 2010;de Kovel et al, 2010;Pregelj, 2011;Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011;Shi et al, 2011;Yue et al, 2011]. This has led to a shift to the discovery of rarer genetic variation including CNV as a potential source for the missing heritability [Manolio et al, 2009].…”

Immuno-epileptology

“…Epilepsies are collectively the most commonly seen neurological conditions to which a lot of stigma is attached. They are complex conditions which appear to be associated with rare genetic variants (including copy number variants, single-nucleotide polymorphisms, de novo mutations, and genomic hotspots) rather than common genetic loci [2][3][4]. Shared genetic loci between epilepsy and neurodevelopmental disorders explain the increased occurrence of epilepsies in patients with neurodevelopmental disorders, especially autism [5] and fragile X syndrome [6], and that it is in support of the viewpoint that epilepsy is a chronic neurodevelopmental disorder [7].…”