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-sampleMendelian 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>1million 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 serumcalciumlevels (39,400 subjects). We observed co-occurrence ofmigraine 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 (r g =0.191, P=0.03) between serum calciumand migraine headache, indicating that these traits have a genetic basis in common. Finally, we found that elevation of serum calciumlevels by 1 mg/dl resulting from our genetic score was associated with an increase in risk ofmigraine (OR=1.80, 95% CI: 1.31-2.46, P=2.5 × 10 -4 ), evidence supporting a causal hypothesis. We also presentmultipleMR sensitivity analyses in support of this central finding. Our results provide evidence that hypercalcaemia is comorbid withmigraine headache diagnoses, and that genetically elevated serumcalcium over lifetime appears to increase risk formigraine. Further studies will be required to understand the biologicalmechanism, pathways, and clinical implication for riskmanagement.