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

Bendik S Winsvold,Yunpeng Wang,John-Anker Zwart,Dale R Nyholt,Verneri Anttila,Aarno Palotie,The International Headache Genetics Consortium ,Arn M J M Van Den Maagdenberg,Tobias Kurth,Daniel I Chasman,Tobias M Freilinger,Gisela M Terwindt,Aree Witoelar,Oleksander Frei,Anders M Dale,Francesco Bettella,Alexey Shadrin,Padhraig Gormley,Ole A Andreassen

doi:10.1371/journal.pone.0185663

Abstract

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.

Highlights

Migraine is a recurrent pain condition which affects some 14% of the general population and is ranked as the 7th leading cause of disability worldwide [1,2,3]
We found significant enrichment of genetic variants associated with coronary artery disease (CAD) as a function of their association with migraine, which was replicated across two independent CAD genome-wide association studies (GWAS) studies
EQTL P-value 7.2E-16 4.3E-12 8.6E-7 4.4E-16 1.2E-11 3.4E-8 1.4E-5. In this large study based on data from 59,773 subjects with migraine or CAD we show that genetic variants associated with migraine are associated with CAD in excess of what would be expected by chance

Summary

Introduction

Migraine is a recurrent pain condition which affects some 14% of the general population and is ranked as the 7th leading cause of disability worldwide [1,2,3]. In about one third of patients, headache attacks are preceded by transient neurological symptoms, termed migraine aura [2]. The pathogenic mechanisms of migraine are incompletely understood, but the disorder has a considerable genetic component with an estimated heritability of 42% [4]. A similar risk increase has been reported for coronary artery disease (CAD) suggesting a relation between migraine and vascular pathology outside the cerebral circulation [9, 10]. Migraine patients more often report a family history of early CAD, suggesting a possible shared genetic basis between both disorders [11]. Genetic loci associated with migraine appear to be enriched for genes expressed in vascular and smooth muscle tissues, pointing towards vascular mechanisms [12]

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