This study, which is a part of the initiative 'Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide', assesses and presents all existing evidence of the world prevalence and burden of headache disorders. Population-based studies applying International Headache Society criteria for migraine and tension-type headache, and also studies on headache in general and 'chronic daily headache', have been included. Globally, the percentages of the adult population with an active headache disorder are 46% for headache in general, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. Our calculations indicate that the disability attributable to tension-type headache is larger worldwide than that due to migraine. On the World Health Organization's ranking of causes of disability, this would bring headache disorders into the 10 most disabling conditions for the two genders, and into the five most disabling for women.

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.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics, and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads, and prioritize genes for functional follow-up studies.

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The present review of epidemiologic studies on migraine and headache in Europe is part of a larger initiative by the European Brain Council to estimate the costs incurred because of brain disorders. Summarizing the data on 1-year prevalence, the proportion of adults in Europe reporting headache was 51%, migraine 14%, and Ôchronic headacheÕ (i.e. ‡15 days/month or ÔdailyÕ) 4%. Generally, migraine, and to a lesser degree headache, are most prevalent during the most productive years of adulthood, from age 20 to 50 years. Several European studies document the negative influence of headache disorders on the quality of life, and health-economic studies indicate that 15% of adults were absent from work during the last year because of headache. Very few studies have been performed in Eastern Europe, and there are also surprisingly little data on tension-type headache from any country. Although the methodology and the quality of the published studies vary considerably, making direct comparisons between different countries difficult, the present review clearly demonstrates that headache disorders are extremely prevalent and have a vast impact on public health. The data collected should be used as arguments to increase resources to headache research and care for headache patients all over the continent.

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n=453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n=14,923 cases, 47,610 controls), physician diagnosed insomnia in Partners Biobank (n=2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n=83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis, phototransduction and muscle development pathways and of genes expressed in multiple brain regions, skeletal muscle and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary heart disease, depressive symptoms and subjective well-being. One Sentence Summary: We identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.

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 × ...