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 (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10−06) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = −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.
Highlights
When extended to the migraine subtypes: migraine with aura (MA) and migraine without aura (MO), diastolic BP (DBP) was consistently correlated with both MA and MO, whereas systolic BP (SBP) was only marginally correlated with MA
0.009 0.009 0.008 0.008 0.008 0.007 0.008 0.008 0.007 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 rg Genetic correlation, gcov genetic covariance, gcov_se standard error of genetic covariance, LDSC linkage disequilibrium (LD) score regression, GNOVA genetic covariance analyzer, DBP diastolic blood pressure, SBP systolic blood pressure, PP pulse pressure. *P-value was calculated for the genetic correlation in LDSC and for the genetic covariance in GNOVA, P-values are based on two-sided Wald test
P-values are based on two-sided Wald test and used Bonferroni correction. aThe instrumental estimate is corresponding to 10 mmHg increment of blood pressure for the forward direction. bToo few instruments to conduct reverse generalized summary-data-based Mendelian randomization (GSMR) for migraine with aura and without aura. cConditional GSMR was performed by conditioning the exposure on the corresponding covariates
Summary
There was a positive overall genetic correlation of migraine with DBP (rg = 0.11, Wald test P = 3.56 × 10−06) and SBP (rg = 0.06, Wald test P = 0.01), but not PP (rg = −0.01, Wald test P = 0.75) using linkage disequilibrium (LD) score regression (LDSC) (Table 1). Findings for genetic covariance analyzer (GNOVA), which included SNPs with lower minor allele frequency (MAF) than LDSC, were similar with rg of 0.12 (Wald test P = 3.45 × 10−07), 0.07 (Wald test P = 4.64 × 10−03), and 0.00 (Wald test P = 0.94) for DBP, SBP, and PP, respectively (Table 1). Partitioned genetic correlation did not reveal strong contrasts but suggested that shared effects were concentrated in some chromosomes with the
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