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Nat Commun. 2018 Dec 10;9(1):5269. doi: 10.1038/s41467-018-07524-z.

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies.

Collaborators (158)

Abou-Khalil B, Auce P, Avbersek A, Bahlo M, Balding DJ, Bast T, Baum L, Becker AJ, Becker F, Berghuis B, Berkovic SF, Boysen KE, Bradfield JP, Brody LC, Buono RJ, Campbell E, Cascino GD, Catarino CB, Cavalleri GL, Cherny SS, Chinthapalli K, Coffey AJ, Compston A, Coppola A, Cossette P, Craig JJ, de Haan GJ, De Jonghe P, de Kovel CGF, Delanty N, Depondt C, Devinsky O, Dlugos DJ, Doherty CP, Elger CE, Eriksson JG, Ferraro TN, Feucht M, Francis B, Franke A, French JA, Freytag S, Gaus V, Geller EB, Gieger C, Glauser T, Glynn S, Goldstein DB, Gui H, Guo Y, Haas KF, Hakonarson H, Hallmann K, Haut S, Heinzen EL, Helbig I, Hengsbach C, Hjalgrim H, Iacomino M, Ingason A, Jamnadas-Khoda J, Johnson MR, Kälviäinen R, Kantanen AM, Kasperavičiūte D, Kasteleijn-Nolst Trenite D, Kirsch HE, Knowlton RC, Koeleman BPC, Krause R, Krenn M, Kunz WS, Kuzniecky R, Kwan P, Lal D, Lau YL, Lehesjoki AE, Lerche H, Leu C, Lieb W, Lindhout D, Lo WD, Lopes-Cendes I, Lowenstein DH, Malovini A, Marson AG, Mayer T, McCormack M, Mills JL, Mirza N, Moerzinger M, Møller RS, Molloy AM, Muhle H, Newton M, Ng PW, Nöthen MM, Nürnberg P, O'Brien TJ, Oliver KL, Palotie A, Pangilinan F, Peter S, Petrovski S, Poduri A, Privitera M, Radtke R, Rau S, Reif PS, Reinthaler EM, Rosenow F, Sander JW, Sander T, Scattergood T, Schachter SC, Schankin CJ, Scheffer IE, Schmitz B, Schoch S, Sham PC, Shih JJ, Sills GJ, Sisodiya SM, Slattery L, Smith A, Smith DF, Smith MC, Smith PE, Sonsma ACM, Speed D, Sperling MR, Steinhoff BJ, Stephani U, Stevelink R, Strauch K, Striano P, Stroink H, Surges R, Tan KM, Thio LL, Thomas GN, Todaro M, Tozzi R, Vari MS, Vining EPG, Visscher F, von Spiczak S, Walley NM, Weber YG, Wei Z, Weisenberg J, Whelan CD, Widdess-Walsh P, Wolff M, Wolking S, Yang W, Zara F, Zimprich F.

Abstract

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

PMID:
30531953
PMCID:
PMC6288131
DOI:
10.1038/s41467-018-07524-z
[Indexed for MEDLINE]
Free PMC Article

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