SCOTTSDALE, Arizona — Genetically increased calcium levels could represent a key causal factor underlying susceptibility to migraine headache, suggests a large population-based study showing elevated calcium levels to be a common comorbidity with migraine.
“Our results provide evidence that hypercalcemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over lifetime appears to increase risk for migraine,” reported the authors of the study, recently published in Human Molecular Genetics.
The study was highlighted this week in a talk at the American Headache Society (AHS) 2017 Scottsdale Headache Symposium.
“What’s interesting to consider here is whether it’s simply a matter of the genes that are related to hypercalcemia also being related to migraine, or does hypercalcemia itself have any kind of bearing on migraine,” said presenter Andrew Charles, MD, who is the Meyer and Renee Luskin Chair in Migraine and Headache Studies and director of the UCLA Goldberg Migraine Program at the David Geffen School of Medicine at the University of California Los Angeles, who was not involved in the study.
Serum calcium levels have been shown to have genetic variation at the population level. For this analysis, the authors used electronic health records data and large-scale genetic data sets to evaluate the association between higher serum calcium and migraine.
The study, conducted by a team of international researchers with first author Peter Yin and senior author Benjamin Voight, PhD, from the University of Pennsylvania, Philadelphia, used the approach of Mendelian randomization, in which genetic variants associated with a biomarker of interest — in this case elevated serum calcium — are used to estimate a causal effect on a disease endpoint — in this case, migraine.
“The approach has some analogy to the classic Randomized Control Trial, where genotype operates as the randomized intervention,” they explained.
For the study, co-heritability and causality were assessed by evaluating 23,285 cases with migraine and 94,425 controls in the International Headache Consortium. Circulating serum calcium levels were further evaluated in 39,400 persons.
The results showed that those with migraine were significantly more likely to have hypercalcemia (odds ratio [OR], 1.58), and the association remained significant after adjustment for migraine risk factors (OR, 1.23).
Furthermore, a genetic heritability of elevated serum calcium was significantly associated with a migraine headache heritability (P = .03), suggesting that the two conditions have a common genetic basis.
“[W]e obtained genome-wide association data for both serum calcium levels and migraine headache and estimated genetic correlation between both traits,” the authors reported.
“In this analysis, we observed a moderate genetic correlation between migraine and calcium levels…rejecting the hypothesis that these traits are independent of one another, and evidence that serum calcium levels and migraine headache may have a genetic basis in common.”
In testing the hypothesis that elevated serum calcium levels have a causative role in migraine, the authors found that each hypothetical increase in serum calcium levels of 1 mg/dL from the genetic score was associated with an increased risk for migraine (OR, 1.80).
After further stratification according to aura status, the results showed that the hypothetical increase in serum calcium levels of 1 mg/dL from the genetic score was associated with an increased risk for migraine with aura (OR, 2.66; 95% confidence interval [CI], 1.40 – 5.02) or without aura (OR, 2.57; 95% CI, 1.49 – 4.43).
The results provide evidence of a link between serum calcium and migraine on three key levels, the authors explained.
“[C]omorbidity analysis using electronic health records indicates that diagnoses for migraine and serum calcium (using hypercalcemia as a proxy) occur in patient records together more than expected,” the authors said.
In addition, they write, genetic heritability analysis indicates that serum calcium and susceptibility to migraine headache may have a genetic basis in common.
Finally, they note, “a genetic risk score analysis in the Mendelian Randomization framework indicates that a hypothetical 1 mg/dl genetic increase in serum calcium levels is associated with a 1.8-fold increase in risk of migraine headache.
“Taken collectively, these data support an epidemiological and genetic correlation, and a potentially causal connection between levels of circulating calcium and susceptibility to migraine,” the authors said.
Key limitations of the study include that diagnostic codes of migraine may not reflect a true clinical diagnosis of migraine, and the order of diagnoses could not be determined, leaving open the possibility of reverse causality in addition to confounding from other factors not included in the analysis, the authors noted.
However, other associations with migraine observed in the study, including features of metabolic syndrome and hypothyroidism, are consistent with other observations, they said.
Dr Charles commented that observed shared genetic component in the findings is particularly intriguing.
“What’s interesting is there seems to be this co-heritability between serum calcium and migraine, and the authors concluded that genetically mediated hypercalcemia might actually increase the risk of migraine,” he said.
The findings suggest that serum calcium levels should be on clinicians’ radars in treating patients with migraine.
“I’ve started looking at calcium in my patients,” Dr Charles said. “I can’t say whether I’ve ever really noticed a correlation between hypercalcemia and migraine — that may have been because I wasn’t paying attention, but I think it’s something that’s interesting for us to look at.”
The study was supported by grants to individual researchers by the European Commission FP7 project, the Academy of Finland, the Sigrid Juselius Foundation, the American Heart Association, the National Institutes of Health, and the Medical Research Council. The study’s authors have disclosed no relevant financial relationships. Dr Charles has received grant support from Takeda; has been a consultant for Amgen, Alder, Biohaven, Eli Lilly, eNeura, and Trevena; and is on the Clinical Trial Steering Committee for St. Jude.
American Headache Society (AHS) 2017 Scottsdale Headache Symposium. Presented November 17, 2017.
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