Serum calcium and risk of migraine: a Mendelian randomization study

Abstract

Migraine affects ∼14% of the world’s population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co-heritability analysis, and a two-sample Mendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine headache. Co-morbidity was evaluated using electronic health records obtained from the PennOmics database comprising >1 million patient entries. Genetic co-heritability and causality via MR was assessed using data from the International Headache Consortium (23,285 cases, 95,425 controls) and circulating serum calcium levels (39,400 subjects). We observed co-occurrence of migraine and hypercalcaemia ICD-9 diagnoses (OR = 1.58, P = 4 × 10−13), even after inclusion of additional risk factors for migraine (OR = 1.23, P = 2 × 10−3). Second, we observed co-heritability (rg = 0.191, P = 0.03) between serum calcium and migraine headache, indicating that these traits have a genetic basis in common. Finally, we found that elevation of serum calcium levels by 1 mg/dl resulting from our genetic score was associated with an increase in risk of migraine (OR = 1.80, 95% CI: 1.31–2.46, P = 2.5 × 10−4), evidence supporting a causal hypothesis. We also present multiple MR sensitivity analyses in support of this central finding. Our results provide evidence that hypercalcaemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over lifetime appears to increase risk for migraine. Further studies will be required to understand the biological mechanism, pathways, and clinical implication for risk management.

Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache

“…Our analyses find evidence for a potentially causal relationship between migraine and diastolic blood pressure, and provide modest replication of a calcium association that we previously reported. 29 This leads to the question of whether these putative causal relationships are independent of one another. To answer this question, we first tested for genetic correlation between calcium and diastolic blood pressure using two different blood pressure GWAS: the UKB results and a combined meta-analysis comprising over 1 million individuals.…”

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

“…Data on ANKDD1B and KIAA0040 were limited, but ANKDD1B was previously suggested to have a shared role between migraine and major depressive disorder (MDD) 28 . Other gene-level genetic overlap between migraine and BP included genes (CISD2, DMPK, and C12orf5) that were related to regulation of calcium homeostasis and reactive oxygen species (ROS) 29,30 . TWAS genes with independent effects shared by subtypes of migraine and BP were consistent with findings for overall migraine at ITGB5, while identifying additional associations at HMOX2 for MA and BP, and HVCN1 and MANBA for MO and BP ( Supplementary Figs.…”

Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities

“…was associated with an increase in risk of migraine [odds ratio (OR) 1.80, 95% CI 1.31–2.46, P = 2.4 x 10 −4 ]’, which was supported by their other two methods. 33 The paper then went on to highlight several therapeutic options that may be possible based on this evidence. These included the use of the drug Cinacalcet, which is already approved by the FDA, to antagonize the calcium-sensing receptor (CaSR).…”