on behalf of the Brainstorm consortium 1 7 2 4 UK 2 5

During a 27-month recruitment period, we identified 146 individuals with multiple sclerosis (MS) who have a twin. A single clinician interviewed and examined 105 pairs of twins, and we confirmed zygosity using minisatellite probes. Including two suspected cases, 11 of 44 (25%) monozygotic twin pairs were concordant compared with two of 61 (3%) dizygotic twin pairs--two of 33 (6%) like-sexed and zero of 28 (0%) opposite-sexed. MRI was performed in 64 of 105 co-twins, and showed abnormalities consistent with demyelination in 13% of monozygotic and 9% of dizygotic co-twins who were clinically unaffected. These findings are similar to the results of most previous studies of MS in twins in which zygosity was not unequivocally established and where the majority of clinically unaffected co-twins were not studied by MRI; the difference in concordance rates in monozygotic and dizygotic twins indicates a significant genetic component in the etiology of MS.

Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods:We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results:We found substantial genetic overlap between migraine and IS using all 4 approaches.Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p 5 6.4 3 10 228 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p 5 2.7 3 10 220 for the CE score in MO). Conclusions:Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype. Neurology ® 2015;84:2132-2145 GLOSSARY CE 5 cardioembolic stroke; CPSM 5 cross-phenotype spatial mapping; GWAS 5 genome-wide association studies; IHGC 5 International Headache Genetics Consortium; IS 5 ischemic stroke; LAS 5 large artery stroke; LD 5 linkage disequilibrium; MA 5 migraine with aura; MO 5 migraine without aura; SNP 5 single nucleotide polymorphism; SVD 5 small vessel disease.Migraine is a primary headache disorder characterized by recurrent attacks of severe, often throbbing, headache associated with autonomic dysfunction. Although the majority of patients have migraine without aura (MO), one third have headaches preceded by transient neurologic disturbances (migraine with aura [MA]). 1 Ischemic stroke (IS) is etiologically heterogeneous and a leading cause of premature death and disability. Results of epidemiologic studies show increased risk of IS in migraine patients.3 A large metaanalysis of case-control and observational cohort studies reported an increased risk of IS for patients with MO and MA, 4 whereas more recent meta-analyses reported the association to be restricted to MA. 3,5,6 Pathophysiology linking these neurovascular disorders remains poorly understood; suggested mechanisms include cortical spreading depression, 7 endothelial dysfunction, 8 enhanced platelet activation, 9 and vasoconstriction.

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