Researchers Uncover New Potential Migraine Cause

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Analyses of genome-wide association studies revealed the potential role metabolite levels play in migraine pathophysiology.

By conducting comprehensive pairwise genetic analyses using genome-wide association study (GWAS) summary statistics, researchers from Queensland University of Technology in Australia identified causal genetic links to 3 blood metabolite levels that increase migraine risk.

Metabolites are defined as substances made or used when individuals break down food, drugs, or chemicals. Specifically, lower levels of docosahexaenoic acid (DHA) and a currently uncharacterized metabolite (X–11315), and higher levels of lysophosphatidylethanolamine (LPE[20:4]) were identified as the 3 levels that increase migraine risk.

The findings, which could pave the way for new migraine preventive drugs and therapies, were published in The American Journal of Human Genetics.

Although the exact underlying pathophysiology of migraine is unknown, the condition is hereditary. In addition, “the study of the blood metabolome (a collection of metabolites) in migraine can provide insights into the metabolism and comorbidity underlying disease and identify new diagnostic and therapeutic targets,” the researchers explained.


“For example, higher levels of blood cholesterol and lower levels of high-density lipoprotein cholesterol and its related metabolite, apolipoprotein A1, support the higher risk of cardiovascular diseases in migraine-affected individuals,” they said.

In the current study, the investigators obtained publicly available GWAS summary statistics for 972 blood metabolic traits from 8 studies, published between 2014 and 2019. Furthermore, to better understand the genetic causal effects of identified metabolic traits on migraine, they conducted a separate genome-wide analysis using migraine GWAS summary statistics from the 2016 report of the International Headache Genetics Consortium. Findings were validated using Mendelian randomization.

A total of 316 unique blood metabolite levels were assessed in relation to their impact on migraine risk.

Analyses revealed:

  • Significant genome-wide genetic overlap between migraine and 44 metabolites, mostly lipid and organic acid metabolic traits (FDR < 0.05)
  • 36 metabolites, mostly related to lipoproteins, that have shared genetic influences with migraine at 8 independent genomic loci (posterior probability > 0.9) across chromosomes 3, 5, 6, 9, and 16
  • Observed relationships between genetic factors influencing blood metabolite levels and genetic risk for migraine suggest an alteration of metabolite levels in individuals with migraine
  • Higher levels of fatty acids, except DHA—a very long-chain omega-3—in migraineurs
  • A causally protective role for a longer length of fatty acids against migraine
  • Causal effect for a higher level of LPE(20:4), on migraine, introducing LPE(20:4) as a potential therapeutic target for migraine

“Variations in blood levels of metabolites can be due to diet, lifestyle, and genetics, but they are easy to measure and may be modified using diet planning and supplementation,” said study author Dale Nyholt, PhD.

The studies also identified 14 fatty acids genetically associated with migraine risk, of which 12 are either medium- or long-chain fatty acids. “As migraine is associated with inflammation and a higher risk for cardiovascular diseases, these findings may reflect adverse effects for medium- or long- chain fatty acids in health, as previously reviewed,” the researchers explained.

In addition, lower levels of omega-3 fatty acids—constituting the remaining 2 metabolites of the 14—have been linked with migraine risk among males. Lower levels of DHA have also been associated with inflammation and cardiovascular disorders, 2 conditions also linked with migraine risk.

Because the GWAS summary statistics used in this analysis are from individuals of European ancestry, results may not be generalizable, marking a limitation to the study. Findings should be replicated using data from larger migraine and metabolite GWASs and be validated in randomized controlled trials, the authors wrote.

Overall, all analyses conducted emphasize the importance of lipids in migraine biology, while results suggest consumption of DHA may benefit migraineurs. Because LPE(20:4) is a chemical compound that blocks the production of an anti-inflammatory molecule called anandamide, “if LPE(20:4) is controlled to allow production of more anandamide to reduce inflammation, this could potentially prevent migraine,” Nyholt added.


Tanha HM, Sathyanarayanan A, Nyholt DR; The International Headache Genetics Consortium. Genetic overlap and causality between blood metabolites and migraine. Am J Hum Genet. Published online October 12, 2021. doi:10.1016/j.ajhg.2021.09.011