Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants for this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch patients and 4,580 population-matched controls. We selected SNPs from 12 loci with two or more SNPs with P-values < 1 × 10 −5 for follow-up in 2,508 patients and 2,652 controls. Two loci, i.e. 1q22 (MEF2D) and 3p24 (near TGFBR2) replicated convincingly (P = 4.9 × 10 −4 , P = 1.0 × 10 −4 , respectively). Meta-analysis of the discovery and replication data yielded two additional genome-wide significant (P < 5 × 10 −8 ) loci in PHACTR1 and ASTN2. In addition, SNPs in two previously reported migraine loci in or near TRPM8 and LRP1 significantly replicated. This study reveals the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder. Main textMigraine is a disabling episodic neurovascular brain disorder affecting 12% of the general population [1][2][3][4] . Migraine attacks are typically characterized by severe throbbing unilateral headache and nausea, vomiting and photo-and phonophobia (migraine without aura; MO). In up to one third of patients attacks may be associated with neurological aura symptoms (migraine with aura; MA). Previous genome-wide association studies (GWAS) identified a migraine susceptibility locus on chromosome 8q22, close to MTDH, in the clinic-based International Headache Genetics Consortium (IHGC) MA study 5 and three other loci in or near PRDM16, LRP1, and TRPM8 in the population-based migraine Women's Genome Health Study (WGHS) 6 . For TRPM8 there was suggestive association (P < 1 × 10 −5 ) also in the clinic-based IHGC MA GWAS 5 . Here we report the first GWAS in MO, the most common form of migraine. We analyzed two large samples from headache centres in Germany and the Netherlands including 2,326 MO patients and 4,580 population-matched controls (Supplementary Note and Supplementary Fig. 1). A quantile-quantile plot of the joint analysis ( Supplementary Fig. 2) and an overall inflation factor ( 1000) of 1.03 were used as final quality control measures. The discovery dataset identified one genome-wide significant (P < 5 × 10 −8 ) locus on chromosome 1q22 as well as eleven additional loci containing multiple SNPs with suggestive association (P < 1 × 10 −5 ) (Supplementary Table 1). Eighteen SNPs from these 12 loci were taken forward to the replication stage in four Fig. 1 and Supplementary Table 1). Eight SNPs in six loci showed P-values < 0.05 in the replication study, and five of these SNPs also showed P-values < 5 × 10 −8 in the meta-analysis combining the discovery and replication cohorts (Table 1, Fig. 1 and Supplementary Fig. 3). Four loci (1q22, 3p24, 6p24, 9q33) replicated, although replication was less convincing for loci on 6p24 and 9q33 with replication P-values of 0.012 and 0.018, respectively, although P-values were < 5 × ...

Introduction According to the IHCD-3β classification, chronic migraine (CM) is headache occurring on 15 or more days/month. Episodic migraine (EM) can be divided into low frequency (LFEM) and high frequency (HFEM) depending on the headache days suffered per month. Methods We performed a clinical comparison of migraine characteristics according to monthly headache days suffered. Patients were divided into three groups: LFEM (1-9 headache days/month), HFEM (10-14 headache days/month) and CM (≥15 headache days/month). Results The analysis included 1109 patients. Previously reported differences between EM and CM were replicated. However, there were three times more clinical differences between LFEM and HFEM than between HFEM and CM (15 vs. 6). A new model that takes 10 headache days as a cut-off value for CM would have a minimally higher predictive capacity (72.8%) and no statistical differences (71.8%) when comparing it to the current classification. Conclusions HFEM patients have few clinical differences compared with CM patients. This includes the poor outcomes regarding headache-related disability and impact on daily life. According to these findings, neurologists and headache specialists should consider that the emotional and functional impact in HFEM patients could be as disabling as in those with CM.