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Shared Migraine, Heart Disease Risk Variants Emerge From GWAS

NEW YORK (GenomeWeb) – Some of the same common genetic variants contribute to both migraine headaches and coronary artery disease (CAD), new research suggests.

Members of the International Headache Genetics Consortium (IHGC) considered genotyping profiles for more than 230,000 individuals with or without a history of CAD or migraine headaches who were enrolled in past genome-wide association studies of the two conditions. Their results suggest the heart and headache conditions are linked to some of the same SNPs, though risk variants for one condition may protect against the other.

In particular, the investigators narrowed in on variants at three loci that had significant ties to both conditions. The directional effects differed for migraine and CAD at two of these loci, they noted, including variants at the PHACTR1 gene locus that had particularly pronounced associations with the heart and headache conditions. The results appeared in PLOS One yesterday.

"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," corresponding author Bendik Winsvold, a neurology and clinical medicine researcher affiliated with Oslo University Hospital and the University of Oslo, and his co-authors wrote.

The scientists went on to explain that the PHACTR1 locus "is an attractive focus for future experimental studies to investigate shared pathogenic mechanisms between migraine and vascular disease." The PHACTR1 gene product is found in the brain and arteries, they noted, apparently contributing to everything from synaptic activity and dendritic features to endothelial function and a contributor to blood pressure  called vasomotor tone.

Migraine risk has been linked to risk of CAD and other vascular conditions in the past. For example, they noted that ischemic stroke risk is reportedly enhanced in individuals with migraine headaches.

In an effort to understand the potential vascular or neuronal roots of migraine headaches, the team brought together data from three CAD or migraine meta-analyses: 15,420 CAD cases and 15,062 unaffected controls from the C4D study, a CARDIoGRAM cohort comprised of 22,233 individuals with CAD and 64,762 without, and an IHGC group of 22,120 migraine-affected individuals paired with 91,284 migraine-free controls.

There, the researchers saw enrichment for CAD-related SNPs amongst the variants with possible ties to migraine risk and vice versa — results they verified using cases and controls from two more CAD studies.

Along with overlapping variants at the PHACTR1 locus on chromosome 6, their results suggested that variants in and around the chromosome 6 potassium channel-coding gene KCNK5 are associated with both heart disease and migraine risk. Similarly, both conditions had ties to a chromosome 10 variant near the AS3MT gene that appears to act as an expression quantitative trait locus for AS3MT in heart and adrenal tissue and the ARL3 gene in the cerebellum region of the brain.

"[S]ince the associated risk variants are not necessarily the causal ones," the authors cautioned, "interpretation of directionality may be confounded by haplotype effects, as well as heterozygous advantage, tissue-specificity, or interactions with other genetic variants or environmental factors."

Even so, they noted, "[a] better understanding of the mechanisms underpinning these shared genetic associations could shed light on vascular mechanisms in migraine and give further insights into the pathogenic basis of both disorders."

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