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. 2017 Sep 28;12(9):e0185663.
doi: 10.1371/journal.pone.0185663. eCollection 2017.

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

Bendik S Winsvold  1   2 , Francesco Bettella  2   3 , Aree Witoelar  2   3 , Verneri Anttila  4   5   6 , Padhraig Gormley  5   6   7 , Tobias Kurth  8   9 , Gisela M Terwindt  10 , Tobias M Freilinger  11   12 , Oleksander Frei  2   3 , Alexey Shadrin  2   3 , Yunpeng Wang  2   3 , Anders M Dale  13 , Arn M J M van den Maagdenberg  10   14 , Daniel I Chasman  9   15 , Dale R Nyholt  16 , Aarno Palotie  5   6   7 , Ole A Andreassen  2   3 , John-Anker Zwart  1   2 ; International Headache Genetics Consortium
Affiliations

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

Bendik S Winsvold et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist. 23&Me Inc. (Mountain View, USA) and Decode genetics Inc. (Reykjavik, Iceland) provided support in the form of salaries for some of the authors listed as part of the International Headache Genetics Consortium (see the Funding Statement). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Overview of the included studies.
Fig 2
Fig 2. Genetic cross-phenotype enrichment of CAD conditional on migraine.
(a-b) Conditional Q-Q plot of nominal versus empirical -log10 P-values (corrected for inflation) in CAD as a function of significance of association with migraine at the level of P ≤ 1, P < 0.1, P < 0.01 and P < 0.001. Dotted lines indicate the null-hypothesis. (c-d) Plots showing fold enrichment for association to CAD in a given -log10 P-value bin as a function of association with migraine.
Fig 3
Fig 3. Conjunction FDR Manhattan plots—Shared risk loci between migraine and coronary artery disease (CAD).
SNPs with conjunctional false discovery rate (FDR) < 0.05 are shown with large points. A black line around the large points indicate the most significant SNP in each linkage disequilibrium block, annotated with the closest gene. Separate plots are shown for cross-phenotype loci between a) migraine and C4D, and b) migraine and CARDIoGRAM.
See this image and copyright information in PMC

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