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.
Highlights
IntroductionFurther funding sources include: Wellcome Trust (grant 084730); Epilepsy Society, UK, NIHR (08-08-SCC); GIHE: NIH R01-NS-49306-01 (R.J.B.); NIH R01-NS-053998 (D.H.L); GSCFE: NIH R01-NS-064154-01 (R.J.B. and Ha.Ha.); NIH: UL1TR001070, Development Fund from The Children’s Hospital of Philadelphia (Ha.Ha.); NHMRC Program Grant ID: 1091593 (S.F.B., I.E.S., K.L.O., and K.E.B.); The Royal Melbourne Hospital Foundation Lottery Grant (S.P.); The RMH Neuroscience Foundation (T.J.O’B.); European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279062 (EpiPGX) and 602102, Department of Health’s NIHR Biomedical Research Centers funding scheme, European Community (EC: FP6 project EPICURE: LSHM-CT2006-037315); German Research Foundation (DFG: SA434/4-1/4-26-1 (Th.Sa.), WE4896/3-1); EuroEPINOMICS Consortium (European Science Foundation/DFG: SA434/5-1, NU50/8-1, LE1030/11-1, HE5415/3-1 (Th.Sa., P.N., H.L., I.H.), RO 3396/21); the German Federal Ministry of Education and Research, National Genome Research Network (NGFNplus/EMINet: 01GS08120, and 01GS08123 (Th.Sa., H.L.); IntenC, TUR 09/I10 (Th.Sa.)); The Netherlands National Epilepsy Fund (grant 04-08); EC (FP7 project EpiPGX 279062)
We found a novel genome-wide significant association with juvenile myoclonic epilepsy (JME) and two novel loci associated with focal epilepsy with hippocampal sclerosis
The results suggest that the expression of genes associated with focal epilepsy is up-regulated in late-infancy and young adulthood, whereas expression of those genes associated with genetic generalized epilepsy is down-regulated in early childhood and differentially expressed prenatally and at adolescence (Supplementary Fig. 13)
Summary
Further funding sources include: Wellcome Trust (grant 084730); Epilepsy Society, UK, NIHR (08-08-SCC); GIHE: NIH R01-NS-49306-01 (R.J.B.); NIH R01-NS-053998 (D.H.L); GSCFE: NIH R01-NS-064154-01 (R.J.B. and Ha.Ha.); NIH: UL1TR001070, Development Fund from The Children’s Hospital of Philadelphia (Ha.Ha.); NHMRC Program Grant ID: 1091593 (S.F.B., I.E.S., K.L.O., and K.E.B.); The Royal Melbourne Hospital Foundation Lottery Grant (S.P.); The RMH Neuroscience Foundation (T.J.O’B.); European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279062 (EpiPGX) and 602102, Department of Health’s NIHR Biomedical Research Centers funding scheme, European Community (EC: FP6 project EPICURE: LSHM-CT2006-037315); German Research Foundation (DFG: SA434/4-1/4-26-1 (Th.Sa.), WE4896/3-1); EuroEPINOMICS Consortium (European Science Foundation/DFG: SA434/5-1, NU50/8-1, LE1030/11-1, HE5415/3-1 (Th.Sa., P.N., H.L., I.H.), RO 3396/21); the German Federal Ministry of Education and Research, National Genome Research Network (NGFNplus/EMINet: 01GS08120, and 01GS08123 (Th.Sa., H.L.); IntenC, TUR 09/I10 (Th.Sa.)); The Netherlands National Epilepsy Fund (grant 04-08); EC (FP7 project EpiPGX 279062). The International League Against Epilepsy (ILAE) facilitated the Consortium through the Commission on Genetics and by financial support; the opinions expressed in the manuscript do not necessarily represent the policy or position of the I
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