A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine

Abstract

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N_cases/N_controls = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, r_g = 0.11, P = 3.56 × 10^-06) and systolic BP (SBP, r_g = 0.06, P = 0.01), but not pulse pressure (PP, r_g = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10^-08), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10^-25) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10^-07) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10^-07). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.

Fig. 1. Local genetic correlation between migraine and BP traits at reported migraine loci using ρ-HESS and GWAS-PW.

Colors represent the significance level of local genetic correlation between migraine and blood pressure (BP) traits (DBP, SBP, and PP) using ρ-HESS (P_ρ-HESS based on Wald test), red for positive genetic correlation and blue for negative genetic correlation at the corresponding locus. Dots represent the estimated posterior probability (PPA_3) that genetic associations with migraine and BP traits (DBP, SBP, and PP) co-localize at the corresponding locus, larger size indicate larger posterior probability. Significant local genetic correlation between BP traits and migraine was observed at three regions: harboring gene FHL5, C7orf10, and PLCE1, after controlling for multiple testing (P_ρ-HESS < 0.05/1703, see details in Supplementary Table 1) and with high estimated posterior probability (PPA_3 > 0.9, see details in Supplementary Table 2).

Fig. 2. Number of shared TWAS significant genes between migraine and BP traits across 48 GTEx tissues (version 7).

The X axis shows the count of genes from tissues in the GTEx database meeting significance thresholds for multiple testing for migraine and for each of the BP measures as indicated. The Y axis lists GTEx tissues. Colors represent different tissue categories. The null hypothesis of TWAS is no expression-trait association (or genetic correlation between expression and a trait) conditional on the observed GWAS statistics at the corresponding locus. The total number of TWAS gene-tissue pairs being tested is 206,397 across 48 GTEx tissues. TWAS transcriptome-wide association studies, BP blood pressure, DBP diastolic blood pressure, SBP systolic blood pressure, PP pulse pressure, No. number.