Molecular genetic overlap between migraine and major depressive disorder.

Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h2 = 12%) and MDD (h2 = 19%), and a significant cross-disorder genetic correlation (rG = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome-wide significant association (PSNP ≤ 5 × 10-8) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (Pgene-based ≤ 0.05) with both migraine and MDD (Pbinomial-test = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher's combined gene-based P values that surpassed the genome-wide significance threshold (PFisher's-combined ≤ 3.6 × 10-6). Pathway analysis of genes with PFisher's-combined ≤ 1 × 10-3 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD.

Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants.

Migraine is a recurrent pain condition traditionally viewed as a neurovascular disorder, but little is known of its vascular basis. In epidemiological studies migraine is associated with an increased risk of cardiovascular disease, including coronary artery disease (CAD), suggesting shared pathogenic mechanisms. This study aimed to determine the genetic overlap between migraine and CAD, and to identify shared genetic risk loci, utilizing a conditional false discovery rate approach and data from two large-scale genome-wide association studies (GWAS) of CAD (C4D, 15,420 cases, 15,062 controls; CARDIoGRAM, 22,233 cases, 64,762 controls) and one of migraine (22,120 cases, 91,284 controls). We found significant enrichment of genetic variants associated with CAD as a function of their association with migraine, which was replicated across two independent CAD GWAS studies. One shared risk locus in the PHACTR1 gene (conjunctional false discovery rate for index SNP rs9349379 < 3.90 x 10-5), which was also identified in previous studies, explained much of the enrichment. Two further loci (in KCNK5 and AS3MT) showed evidence for shared risk (conjunctional false discovery rate < 0.05). The index SNPs at two of the three loci had opposite effect directions in migraine and CAD. Our results confirm previous reports that migraine and CAD share genetic risk loci in excess of what would be expected by chance, and highlight one shared risk locus in PHACTR1. Understanding the biological mechanisms underpinning this shared risk is likely to improve our understanding of both disorders.

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about 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 carried out a genetic study of migraine on 59,674 affected subjects 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 mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be 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.

Prevalence of nonstenosing, complicated atherosclerotic plaques in cryptogenic stroke.

OBJECTIVES: Our goal was to assess the prevalence of complicated American Heart Association (AHA) lesion type VI plaques in the carotid arteries of patients with cryptogenic stroke. BACKGROUND: In up to 40% of ischemic stroke patients, no definite cause can be established despite extensive workup (i.e., cryptogenic stroke). To test the hypothesis if nonstenosing complicated carotid plaques may be the underlying etiology in some of these patients, we used high-resolution black-blood carotid magnetic resonance imaging (MRI), which can quantitatively assess plaque composition and morphology with good correlation to histopathology. Specifically, we focused on AHA type VI plaques, which are characterized by hemorrhage, thrombus, or fibrous cap rupture. METHODS: Thirty-two consecutive patients (22 male; mean age 71.7 ± 11.9 years) with cryptogenic stroke and nonstenosing (<50%) eccentric carotid plaques were recruited from a single stroke unit. All patients underwent extensive clinical workup (brain MRI, duplex sonography, electrocardiography and Holter monitoring, transthoracic and transesophageal echocardiography, and laboratory investigations) to exclude other causes of stroke. All patients received a black-blood carotid MRI at 3-T with fat-saturated pre- and post-contrast T-1-, proton density-, and T-2-weighted and time-of-flight images using surface coils and parallel imaging techniques. Prevalence of AHA type VI plaque was determined in both carotid arteries on the basis of previously published MRI criteria. RESULTS: AHA type VI plaques were found in 12 of 32 arteries (37.5%) ipsilateral to the stroke, whereas there were no AHA type VI plaques contralateral to the stroke (p = 0.001). The most common diagnostic feature of AHA type VI plaques was intraplaque hemorrhage (75%), followed by fibrous plaque rupture (50%) and luminal thrombus (33%). CONCLUSIONS: This pilot study suggests that arterio-arterial embolism from complicated, nonstenosing carotid atherosclerotic plaques may play a role in a subgroup of patients previously diagnosed with cryptogenic stroke. To further evaluate the significance of AHA type VI plaques in cryptogenic stroke, future studies will have to analyze both clinical and imaging follow-up data, including event rates for secondary strokes.