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The aim of this large cross-sectional population-based study was to examine the association between migraine, non-migrainous headache and headache frequency with depression, and anxiety disorders. From 1995 to 1997, all 92 566 inhabitants aged 20 years and above in Nord-Trøndelag County in Norway were invited to participate in the Nord-Trøndelag Health Study ('Helseundersøkelsen i Nord-Trøndelag' = HUNT-2). A total of 64 560 participated, whereof 51 383 subjects (80%) completed a headache questionnaire that was included. Of these 51 383 individuals, 47 257 (92%) completed the depression subscale items and 43 478 (85%), the anxiety subscale items of the Hospital Anxiety and Depression Scale (HADS). Associations were assessed in multivariate analyses, estimating prevalence odds ratios (OR) with 95% confidence intervals (CI). Depression and anxiety disorders as measured by HADS, were significantly associated with migraine (OR = 2.7, 95% CI 2.3-3.2; OR = 3.2, 95% CI 2.8-3.6) and non-migrainous headache (OR = 2.2, 95% CI 2.0-2.5; OR = 2.7, 95% CI 2.4-3.0) when compared with headache-free individuals. The association was stronger for anxiety disorders than for depression. The ORs for depression and anxiety disorders amongst both migraine and non-migrainous sufferers increased with increasing headache frequency. Depression and anxiety disorders are associated with both migraine and non-migrainous headache, and this association seems more dependent on headache frequency than diagnostic category.

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.