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Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

Anney, Richard, Avbersek, A., Balding, D., Baum, L., Becker, F., Berkovic, S. F., Bradfield, J. P., Brody, L. C., Buono, R. J., Catarino, C. B., Cavalleri, G. L., Cherny, S. S., Chinthapalli, K., Coffey, A. J., Compston, A., Cossette, P., de Haan, G-J., De Jonghe, P., de Kovel, C. G. F., Delanty, N., Depondt, C., Dlugos, D. J., Doherty, C. P., Elger, C. E., Ferraro, T. N., Feucht, M., Franke, A., French, J., Gaus, V., Goldstein, D. B., Gui, H., Guo, Y., Hakonarson, H., Hallman, K., Heinzen, E. L., Helbig, I., Hjalgrim, H., Jackson, M., Jamnadas-Khoda, J., Janz, D., Johnson, M. R., Kalviainen, R., Kantanen, A-M., Kasperaviciute, D., Kasteleijn-Nolst Trenite, D., Koeleman, B. P. C., Kunz, W. S., Kwan, P., Lung Lau, Y., Lehesjoki, A-E., Lerche, H., Leu, C., Lieb, W., Lindhout, D., Lo, W., Lowenstein, D. H., Malovini, A., Marson, A. G., McCormack, M., Mills, J. M., Moerzinger, M., Moller, R. S., Molloy, A. M., Muhle, H., Newton, M., Ng, P-W., Nothen, M. M., Nurnberg, P., O'Brien, T. J., Oliver, K. L., Palotie, A., Pangilinan, F., Pernhorst, K., Petrovski, S., Privitera, M., Radtke, R., Reif, P. S., Rosenow, F., Ruppert, A-K., Sander, T., Scattergood, T., Schachter, S., Schankin, C., Scheffer, I. E., Schmitz, B., Schoch, S., Sham, P. C., Sisodiya, S., Smith, D. F., Smith, Philip E. M., Speed, D., Sperling, M. R., Steffens, M., Stephanie, U., Striano, P., Stroink, H., Surges, R., Tan, K. M., The KORA Study Group, , Thomas, G. N., Todaro, M., Tostevin, A., Tozzi, R., Trucks, H., Visscher, F., von Spiczak, S., Walley, N. M., Weber, Y. G., Wei, Z., Whelan, C., Yang, W., Zara, F. and Zimprich, F. 2014. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. The Lancet Neurology 13 (9) , pp. 893-903. 10.1016/S1474-4422(14)70171-1

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Abstract

Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10−8. Findings We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes).

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Additional Information: Authors are all part of the International League Against Epilepsy Consortium on Complex Epilepsies.
Publisher: Elsevier
ISSN: 1474-4422
Last Modified: 04 Jun 2017 08:50
URI: http://orca-mwe.cf.ac.uk/id/eprint/85893

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