Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study

Cavalleri, Gianpiero L.; Weale, Michael E.; Shianna, Kevin V.; Singh, Rinki; Lynch, John; Grinton, Bronwyn E.; Szoeke, Cassandra; Murphy, Kevin; Kinirons, Peter; O’Rourke, Deirdre; Ge, Dongliang; Depondt, Chantal; Claeys, Kristl G.; Pandolfo, Massimo; Gumbs, Curtis; Walley, Nicole M.; McNamara, James O; Mulley, John C.; Linney, Kristen N.; Sheffield, Leslie J.; Radtke, Rodney A.; Tate, Sarah K.; Chissoe, Stephanie L.; Gibson, Rachel A.; Hosford, David A.; Stanton, Alice; Graves, Tracey D.; Hanna, Michael G.; Eriksson, Kai; Kantanen, Anne Mari; Kälviäinen, Reetta; O’Brien, Terence J.; Sander, Josemir W.; Duncan, John S.; Scheffer, Ingrid E.; Berkovic, Samuel F.; Wood, Nicholas W.; Doherty, Colin; Delanty, Norman; Sisodiya, Sanjay M.; Goldstein, David B.

doi:10.1016/s1474-4422(07)70247-8

Cited by 169 publications

(121 citation statements)

References 25 publications

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“…The reason a number of high LD SNP pairs do occur is that in addition to selected tag SNPs, a number of functional SNPs were selected for analysis at these genes, irrespective of their LD relationship with neighbouring SNPs. 3 The r 2 values for these SNP pairs in the European HapMap population were correlated to the r 2 values calculated for the same SNP pairs in each of the four test populations (Figure 4). Overall, the Irish (P ¼ 0.0004) and UK (P ¼ 0.0002) populations had the highest correlations for portable tags, with the Finnish population showing the least portability.…”

Section: Genetic Mapping In Irelandmentioning

confidence: 85%

“…Variation across the 279 candidate genes that was determined as functional was genotyped directly, regardless of LD or presence in HapMap data set. For a description of 'functionality' as used here, and the full list of SNPs considered in this study see Cavalleri et al 3 …”

Section: Selection Of Candidate Genes and Snpsmentioning

confidence: 99%

“…We have recently completed a large-scale candidate gene association study for epilepsy. 3 One of the central questions surrounding the utility of HapMap project data in association study design is how well the pattern of LD in the four reference populations (ie, Caucasian, Han Chinese, Japanese and Yoruban) matches the study population, in other words, how transferable or portable are tagging SNPs (tSNPs) selected in HapMap to the particular population being examined. A number of analyses of haplotypic variation and portability of SNPs derived from HapMap have recently been carried out.…”

Section: Introductionmentioning

confidence: 99%

“…We have carried out this analysis to (a) assess the suitability of each population for use in genetic association studies where, as is often the case, the European HapMap sample is the reference panel used for choosing tSNPs and (b) inform on population structure between populations used in a recent genetic mapping effort in epilepsy. 3 With the exception of the HapMap population, this study is based solely on data generated in healthy control samples which formed part of a large-scale genetic association study of epilepsy. 3 In total, 4424 SNPs were genotyped in 1118 healthy individuals from Ireland, the UK, Finland and Australia.…”

Section: Introductionmentioning

confidence: 99%

“…3 With the exception of the HapMap population, this study is based solely on data generated in healthy control samples which formed part of a large-scale genetic association study of epilepsy. 3 In total, 4424 SNPs were genotyped in 1118 healthy individuals from Ireland, the UK, Finland and Australia. We investigated (a) the degree to which allele frequency and LD values in each population correlated with those observed in the HapMap reference sample, (b) the extent of haplotype diversity in each population, (c) the degree of differentiation between the populations and (d) the transferability of tags across each of the populations.…”

Section: Introductionmentioning

confidence: 99%

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An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases

et al. 2007

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The recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly and easily selected and consequently HapMap data are regularly applied to both small-and large-scale genetic mapping studies. However, to correctly interpret the application of HapMap-derived tSNPs in a genetic mapping study, an understanding of how well HapMap data represents LD in the study population is critical. The Irish population had not previously been characterised in this way. Here, we do so using a set of 4424 SNPs selected from 279 candidate genes for epilepsy genotyped across 1118 healthy individuals from the Irish, British, Finnish and Australian populations. By considering the Irish population alongside surrounding European populations, our results confirm that the HapMap European-derived population accurately estimates patterning of LD in European descent populations. The Irish population appears notably well matched to the European HapMap population, and is markedly similar to the neighbouring British population. Although we were unable to detect significant substructure within the Irish population (a favourable result for genetic mapping), methods for controlling stratification should always be incorporated. This analysis therefore confirms that the genetic architecture of the Irish population is well suited to the study of complex traits and that tSNPs selected using the HapMap data can be confidently applied to the Irish population.

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Section: Genetic Mapping In Irelandmentioning

confidence: 85%

Section: Selection Of Candidate Genes and Snpsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases

et al. 2007

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Clinical Significance of Rare Copy Number Variations in Epilepsy

et al. 2012

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Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy

Perucca

Stanley

Harris

et al. 2023

Annals of Neurology

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Objective Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. Methods We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug‐resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2‐year postsurgical follow‐up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. Results Nine centers from 3 continents contributed 206 patients operated for drug‐resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss‐of‐function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9–3.5, p = 1.3E‐09) and in genes encoding voltage‐gated cation channels (OR = 2.4, 95% CI = 1.4–3.8, p = 2.7E‐04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between‐group differences. Interpretation Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision‐making and counseling. ANN NEUROL 2023;93:752–761

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Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study

Cited by 169 publications

References 25 publications

An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases

An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases

Clinical Significance of Rare Copy Number Variations in Epilepsy

Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy

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