Meta-Analysis Outlines Interrelationship of Migraine, Blood Pressure

Positive genetic correlations of migraine with diastolic blood pressure (BP) and systolic BP exist, supporting the notions that diastolic BP plays a critical role in migraine susceptibility and BP and migraine share underlying biological mechanisms, according to a study published in Nature Communications.

The link between migraine and the vascular system has been substantiated by numerous studies yielding physiologic and epidemiologic evidence, the authors write, including migraine comorbidities of vascular conditions such as stroke and coronary artery disease.

Genome-wide association studies (GWAS) have also found “approximately 40% of the genome-wide significant GWAS loci for migraine map near genes with known or suspected vascular functions, including vascular development, endothelial structure, and smooth muscle function.”

BP-lowering medications have also been shown to provide prophylactic benefit to many migraineurs. However, associations of BP with migraine are not consistent. To gain insight into mechanistic links between BP and migraine, the researchers leveraged large-scale genetic summary-level data and applied preceding genetic methods.

Using the most recent GWAS summary-level data from the International Headache Genetics Consortium for migraine, the researchers conducted a meta-analysis on 59,674 cases and 316,078 controls from 22 cohort-level GWASs. BP meta-analysis summary statistics combined 757,601 participants from the United Kingdom Biobank (n = 458,577) and International Consortium of Blood Pressure GWASs (n = 299,024 across 77 cohorts).

Conventional cross-trait linkage disequilibrium score regression (LDSC) and the genetic covariance analyzer were used to evaluate genetic correlation between migraine and BP, while transcriptome-wide association studies (TWAS) were used to identify genes whose expression pattern across tissues implicated etiology or biological mechanisms shared by migraine and BP measures.

Analyses revealed:

• A positive overall genetic correlation of migraine with diastolic BP (r_g = 0.11; Wald test P = 3.56 × 10⁻⁰⁶) and systolic BP (r_g = 0.06; Wald test P = .01), but not pulse pressure (r_g = −0.01; Wald test P = .75) using LDSC
• Diastolic BP was consistently correlated with both migraine with aura (r_g = 0.17; Wald test P = 1.50 × 10⁻⁰³) and migraine without aura (r_g = 0.14; Wald test P = 1.20 × 10⁻⁰³), whereas systolic BP was only marginally correlated with migraine with aura (r_g = 0.10; Wald test P = .04)
• Partitioned genetic correlation suggested that shared effects were concentrated in some chromosomes, with the strongest positive genetic correlation observed at chromosome 22 (r_g = 0.47; Wald test P = 1.37 × 10⁻⁰⁴) between migraine and diastolic BP, and the strongest negative genetic correlation observed at chromosome 19 (r_g = −0.32; Wald test P = 1.28 × 10⁻⁰³) between migraine and pulse pressure
• Genome-wide significant local genetic correlation existed between migraine and BP at 3 regions, while for pulse pressure, the overall genome-wide genetic correlation with migraine was null

The strongest association was found between elevated diastolic BP and increased migraine susceptibility. However, “weaker genetic relationships of elevated systolic BP with migraine were largely explained by effects on diastolic BP, and conditional on diastolic BP, genetically determined systolic BP was inversely related to migraine susceptibility.”

The researchers also found 9 replicating single nucleotide polymorphisms (SNPs) from cross-trait association analysis, in addition to 12 genes from TWAS of both migraine and BP, which suggested potential functions relevant to migraine, the authors write.

“The 5 loci identified in both SNP and TWAS analysis revealed potential shared biological mechanisms in migraine and BP regulation involving vascular development and endothelial function, neurogenic inflammation, and calcium homeostasis,” they stated.

One limitation to the study is its relegation of general susceptibility of migraine to the condition’s major subtypes of migraine with and without aura. As such, results may not extend to different migraine traits over time or other forms of migraine. More work is also needed to identify individual cell types and detailed molecular mechanisms that contribute to the relationship, apart from the tissues and genes included in the current study.

“The findings further our understanding of the long-standing debate about the role of BP in migraine susceptibility, reveal the prominent genetic-based role of diastolic BP in migraine susceptibility, and identify shared genetic components including ADRA2B, all of which may provide insight into future migraine therapies,” researchers conclude.

Reference

Guo Y, Rist PM, Daghlas I, Giulianna F, Kurth T, Chasman DI; The International Headache Genetics Consortium, The 23andMe Research Team. A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine. Nat Commun. Published online July 6, 2020. doi:10.1038/s41467-020-17002-0