title: 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.
authors.affiliation: Department of Biology, College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Yin
authors.affiliation: Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.affiliation: Genomics and Computational Biology Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Siewert
authors.affiliation: Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
mesh_terms: D000328:Adult; D000368:Aged; D002118:Calcium / Q000097:blood*; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000235:genetics; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D008881:Migraine Disorders / Q000097:blood / Q000235:genetics; D019655:Quantitative Trait, Heritable
chemical_list: D002118:Calcium