Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 44 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures, and ataxia. We exome-sequenced 84 unrelated PME patients of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation c.959G>A (p.Arg320His) in KCNC1 was identified as a novel major cause for PME. Eleven unrelated exome-sequenced (13%) and two patients in a secondary cohort (7%) had this mutation. KCNC1 encodes K V 3.1, a subunit of the K V 3 voltage-gated K + channels, major determinants of high-frequency neuronal firing. Functional analysis of the p.Arg320His mutant channel revealed a dominant-negative loss-of-function effect. Ten patients had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6, SERPINI1). Identification of mutations in PRNP, SACS, and TBC1D24 expand their phenotypic spectrum to PME. These findings provide important insights into the molecular genetic basis of PME and reveal the role of de novo mutations in this disease entity.Correspondence should be addressed to Anna-Elina Lehesjoki (anna-elina.lehesjoki@helsinki.fi). Author Contributions Accession codesMutation nomenclatures correspond to the following canonical Ensembl transcripts: KCNC1, ENST00000265969.6; NEU1, ENST00000375631.4; NHLRC1, ENST00000340650.3; EPM2A, ENST00000367519.3; CLN6, ENST00000249806.5; AFG3L2, ENST00000269143.3; TBC1D24, ENST00000293970.5; SACS, ENST00000382298.3; SERPINI1, ENST00000295777.5; PRNP, ENST00000379440.4; SCN1A, ENST00000303395.4. The raw aligned sequence reads were submitted to the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home) by Wellcome Trust Sanger Institute under study accession numbers EGAS00001000048 and EGAS00001000386. Competing Financial InterestsAuthors declare no potential competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2015 July 01. Published in final edited form as:Nat Genet. 5,6 and GOSR2 7 also contribute to cases of PME with preserved cognition. Other PMEs may have additional features, particularly dementia. PME-associated genes encode a variety of proteins, many of them being associated with endosomal and lysosomal function 8,9 , but the associated disease mechanisms are generally poorly understood.The precise clinical diagnosis of specific forms of PME is challenging due to their genetic heterogeneity, phenotypic similarities and overlap of symptoms with other epileptic and neurodegenerative diseases. In many cases, there are no distinguishing clinical features or biomarkers. Consequently, a substantial proportion of PME cases remain without a molecular diagnosis 3 .Here, we aimed to identify the causative genes for unsolved PME cases by employing exome sequencing in unrelated patients assembled from multiple centers in Europe, North America, Asia, and Australia over a 25-year period. The extent of previous molecular studies varied, but all cases were negative for mutations in the ...