Claudia M. Weller

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10−9, odds ratio = 1.23, 95% CI 1.150–1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10−11 (odds ratio = 1.18, 95% CI 1.127–1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10−5, permuted threshold for genome-wide significance 7.7 × 10−5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Genome-wide meta-analysis identifies new susceptibility loci for migraine

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 × 10−8). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Mutations in DEPDC5 cause familial focal epilepsy with variable foci

The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions. Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction.

Migraine is not associated with enhanced atherosclerosis

Aim Migraine, in particular with aura, has been associated with an increased risk for ischemic stroke and coronary heart disease. The underlying mechanism is unknown. In a cross-sectional case control study we investigated whether an enhanced risk of atherosclerosis in migraineurs explains this increased cardiovascular risk. Methods Subjects were participants from the population-based Erasmus Rucphen Family study. Atherosclerosis was assessed in 360 migraineurs (209 without aura and 151 with aura) and 617 subjects without migraine or severe headache. Atherosclerosis was quantified by intima media thickness, pulse wave velocity and ankle-brachial index. Results Migraineurs, especially with aura, were found more likely to smoke, have diabetes or a modestly decreased HDL-cholesterol. No differences were found for the atherosclerosis parameters. Conclusion In this large population-based study, migraineurs have no increased risk of atherosclerosis. Therefore, enhanced atherosclerosis is an unlikely explanation for the increased cardiovascular risk seen in migraineurs.

Cluster headache and the hypocretin receptor 2 reconsidered: A genetic association study and meta-analysis

Background Cluster headache is a severe neurological disorder with a complex genetic background. A missense single nucleotide polymorphism (rs2653349; p.Ile308Val) in the HCRTR2 gene that encodes the hypocretin receptor 2 is the only genetic factor that is reported to be associated with cluster headache in different studies. However, as there are conflicting results between studies, we re-evaluated its role in cluster headache. Methods We performed a genetic association analysis for rs2653349 in our large Leiden University Cluster headache Analysis (LUCA) program study population. Systematic selection of the literature yielded three additional studies comprising five study populations, which were included in our meta-analysis. Data were extracted according to predefined criteria. Results A total of 575 cluster headache patients from our LUCA study and 874 controls were genotyped for HCRTR2 SNP rs2653349 but no significant association with cluster headache was found (odds ratio 0.91 (95% confidence intervals 0.75–1.10), p = 0.319). In contrast, the meta-analysis that included in total 1167 cluster headache cases and 1618 controls from the six study populations, which were part of four different studies, showed association of the single nucleotide polymorphism with cluster headache (random effect odds ratio 0.69 (95% confidence intervals 0.53–0.90), p = 0.006). The association became weaker, as the odds ratio increased to 0.80, when the meta-analysis was repeated without the initial single South European study with the largest effect size. Conclusions Although we did not find evidence for association of rs2653349 in our LUCA study, which is the largest investigated study population thus far, our meta-analysis provides genetic evidence for a role of HCRTR2 in cluster headache. Regardless, we feel that the association should be interpreted with caution as meta-analyses with individual populations that have limited power have diminished validity.

PRRT2 mutation causes benign familial infantile convulsions

Benign familial infantile convulsions (BFIC) is an autosomal dominantly inherited epilepsy syndrome with onset between 3 and 12 months of age. It is characterized by brief seizures with motor arrest, cyanosis, hypertonia, and limb jerks. Seizures respond well to antiepileptic drugs and remission occurs before the age of 3 years.1 Several recent publications described heterozygous mutations in the proline-rich transmembrane protein 2 (PRRT2) gene on chromosome 16p11.2, one of the known BFIC loci,2,3 in an increasingly large number of families with paroxysmal kinesigenic dyskinesia (PKD) and PKD with infantile convulsions (PKD/IC).4-6 The majority of PRRT2 mutations result in a premature truncation of PRRT2 protein. Although its exact function is unknown, recent studies indicated that PRRT2 is highly expressed in the developing nervous system and localized in axons in primary neuronal cultures.6 Through binding to synaptic protein SNAP25, PRRT2 may be involved in vesicle docking and calcium-triggered neuronal exocytosis.6 Preliminary functional studies of truncated PRRT2 mutants showed either a loss of membrane localization in COS-7 cells5 or near absence of mutant protein in hippocampal neuronal cultures6 that is likely due to nonsense mediated RNA decay. One can speculate that mutant PRRT2 protein may result in abnormal neurotransmitter release and neuronal hyperexcitability that could explain the clinical symptoms seen with PKD and PKD/IC. We tested whether PRRT2 is also the causal gene in families with BFIC without associated paroxysmal dyskinesia.

Cluster‐Tic Syndrome: A Cross‐Sectional Study of Cluster Headache Patients

To determine the prevalence and nature of trigeminal neuralgia in a large group of cluster headache patients.

Stepwise web-based questionnaires for diagnosing cluster headache: LUCA and QATCH

Background Cluster headache (CH) is a primary headache disorder that is diagnosed based on the patients history. For large-scale epidemiologic and genetic studies, a web-based, preferably short, questionnaire can be a feasible alternative to replace time-consuming clinical interviews. Methods Self-reported CH patients were enrolled via our research website. Participants meeting screening criteria were directed to the Leiden University Cluster headache Analysis program (LUCA) questionnaire. Individual diagnoses were calculated using an algorithm based on International Headache Society criteria. Subsequently, semi-structured telephone interviews were carried out to validate the LUCA questionnaire. The shorter Quick Ascertainment of Cluster Headache (QATCH) questionnaire for diagnosing CH was constructed by using logistic regression to select the most predictive questions. Results Via our website 437 self-reported CH patients were recruited. Of these, 291 patients were included in this cross-sectional study. The LUCA questionnaire was valid and accurate. Using logistic regression, three questions (QATCH) provided similar sensitivity (53.8% vs. 57.2%), specificity (88.9% vs. 87.5%), positive predictive value (95.5% vs. 95.9%) and negative predictive value (30.8% vs. 28.8%) compared with the LUCA questionnaire. Conclusion The web-based LUCA questionnaire was accurate and reliable in diagnosing CH among self-reported patients. Males with headache attacks of short duration and long headache-free intervals (months to years) are very likely to have CH.

A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood

Background Hemiplegic migraine (HM) and alternating hemiplegia of childhood (AHC) are rare episodic neurological brain disorders with partial clinical and genetic overlap. Recently, ATP1A3 mutations were shown to account for the majority of AHC patients. In addition, a mutation in the SLC2A1 gene was reported in a patient with atypical AHC. We therefore investigated whether mutations in these genes may also be involved in HM. Furthermore, we studied the role of SLC2A1 mutations in a small set of AHC patients without ATP1A3 mutations. Methods We screened 42 HM patients (21 familial and 21 sporadic patients) for ATP1A3 and SLC2A1 mutations. In addition, four typical AHC patients and one atypical patient with overlapping symptoms of both disorders were screened for SLC2A1 mutations. Results A pathogenic de novo SLC2A1 mutation (p.Gly18Arg) was found in the atypical patient with overlapping symptoms of AHC and hemiplegic migraine. No mutations were found in the HM and the other AHC patients. Conclusion Screening for a mutation in the SLC2A1 gene should be considered in patients with a complex phenotype with overlapping symptoms of hemiplegic migraine and AHC.

Novel SCN1A mutation in the IFMT motif of the α1 subunit of the voltage-gated NaV1.1 channel causing familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a monogenic subtype of migraine with aura. So far three FHM genes are identified; the CACNA1A gene, the ATP1A2 gene and the SCN1A gene.