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.

SummaryBackgroundThe 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).MethodsWe 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.FindingsWe 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.InterpretationThis 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).FundingInternational League Against Epilepsy and multiple governmental and philanthropic agencies.

Abstract-The adaptive changes that develop in the pressure-overloaded left ventricular (LV) myocardium include cardiomyocyte hypertrophy and interstitial fibrosis. Although the former is known to depend to a sizeable extent on sympathetic (over)activity, little information exists whether the same applies to the latter, ie, whether excess catecholamine exposure contributes to the imbalance between collagen deposition by fibroblasts and degradation by matrix metalloproteases (MMPs), eventually leading to LV collagen accumulation. Sprague-Dawley rats were subjected to abdominal aortic banding (B) or sham operation (S) and treated with ␤-blockade (Bb, oral propranolol, 40 mg/kg per day), chemical sympathectomy (Sx, 6-hydroxydopamine, 150 mg/kg intraperitoneal twice per week) or vehicle (Vh). Ten weeks later, systolic blood pressure, LV weight, collagen abundance (computer-aided histology), zymographic matrix metalloproteinase (MMP)-2 activity and its specific tissue inhibitor concentration (TIMP-2) were measured. Both sympathectomy and ␤-blockade failed to attenuate the banding-induced blood pressure elevation but significantly attenuated the attendant LV hypertrophy. As expected, pressure-overload hypertrophy was associated with interstitial fibrosis (collagen: 4.37Ϯ1.23% BVh versus 1.23Ϯ0.44% SVh, PϽ0.05), which was abolished by sympathectomy (2.55Ϯ1.31%, Pϭnot significant versus SSx) but left unchanged by ␤-blockade (4.11Ϯ1.23%, PϽ0.05 versus both SBb and BSx). ␤-blockade, but not sympathectomy, was also associated with an increased TIMP-2/MMP-2 ratio (PϽ0.05), indicating reduced interstitial collagenolytic activity. In separate groups of banded and sham-operated rats, treatment with the ␣-receptor blocker doxazosin (10 mg/kg per day) displayed similar antifibrotic and biochemical effects as sympathectomy. Thus in the course of experimental pressure overload, the sympathetic nervous system plays a major pro-fibrotic role, which is mediated via ␣-adrenergic but not ␤-adrenergic receptors. Key Words: collagen Ⅲ extracellular matrix Ⅲ fibrosis Ⅲ heart failure Ⅲ hypertrophy Ⅲ sympathectomy T here is extensive evidence that sympathetic nerve overactivity consistently accompanies hypertension in its uncomplicated stage and even more so after the progressive development of left ventricular (LV) hypertrophy, dysfunction, and failure. 1,2 This has deleterious consequences on the severity of hypertension itself, because it produces peripheral vasoconstriction, as well as on the heart, because: (1) it favors activation of other potentially cardiotoxic neurohumoral systems (renin-angiotensin system, endothelin, etc) 3,4 ; (2) it increases myocardial oxygen consumption; and (3) it directly exerts toxic (pro-apoptotic, pro-necrotic) effects on the myocardium. 5-7 Accordingly, it is now firmly established that administration of ␤-adrenergic receptor blockers favorably affects hypertension and heart failure, 8 most likely via correction of the aforementioned pathophysiological alterations.However, although it is well documented ...

SUMMARYPartial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy (IGE/GGE), childhood focal epilepsy, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS, rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX1 deletions comprise magnetic resonance imaging (MRI)-negative epilepsy of unknown etiology with frontal and temporal origin (n = 5) and two patients with temporal lobe epilepsy with hippocampal sclerosis. The epilepsies were largely pharmacoresistant but not associated with intellectual disability. Our study extends the phenotypic spectrum of RBFOX1 deletions as a risk factor for focal epilepsy and suggests that exonic RBFOX1 deletions are involved in the broad spectrum of focal and generalized epilepsies. KEY WORDS: Copy number variation, Idiopathic, Genetic, Cryptogenic, Magnet resonance imaging negative, Lesional.Structural genomic copy number variations (CNVs) account for a substantial fraction of the genetic predisposition in about 3% of patients with idiopathic epilepsies. 1 Likewise, exonic deletions of the RBFOX1 gene have been associated with a broad range of neurodevelopmental disorders including autism, generalized epilepsies, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS; or rolandic epilepsy) (for overview see Lal et al.1,2 ). The RBFOX1 protein regulates splicing and expression of many neuronal transcripts by binding the sequence (U)GCAUG to introns flanking the alternative splicing sites. It plays a key role in the control of neuronal excitation in the mammalian brain and influences susceptibility to epilepsy.4,5 Notably, brain-specific homozygous and heterozygous Rbfox1 knockouts in mice do not alter brain morphology but display spontaneous seizures and a dramatic epileptogenic response to kainic acid resulting in status epilepticus. 4 With regard to the increased frequency of exonic RBFOX1 deletions in patients with GGE syndromes and focal childhood epilepsies, the present study examined whether exonic RBFOX1 deletions also increase risk of sporadic forms of common focal epilepsy syndromes with juvenile or adult onset. Subjects and Methods PatientsA total of 807 unrelated and sporadic patients of selfreported European ancestry, diagnosed with focal epilepsy with an onset after the age of 15 gave their written informed consent to be included in the study. Of these, 434 had a ...