Study Finds Genetic Overlap Between Sleep Disturbances, Migraine

The genetic determinants of sleep and migraine partly overlap, according to results of a Mendelian randomization (MR) study published in Annals of Clinical and Translational Neurology. This finding suggests sleep disturbances may causally influence migraine etiology and could be targets for migraine treatment.

Although research has shown sleep disturbances are associated with an increased risk of migraine, the extent of shared underlying biology and direction of a causal relationship between these conditions is unclear, the authors explained.

To further investigate a shared genetic basis between sleep traits and migraine, they leveraged cross-trait linkage disequilibrium score regression and MR using data from the United Kingdom Biobank cohort and the largest genome-wide association study (GWAS) of migraine.

MR is defined as “as a natural experiment whereby individuals are randomly allocated to lifelong greater exposure to a given risk factor (eg, insomnia symptoms) based on their genetic risk, and then the risk of a disease outcome (eg, migraine) as a function of this exposure is measured later in life.”

Genetic data on sleep traits were obtained from both published and unpublished GWAS summary statistics from UK Biobank participants, whereas migraine data were obtained from the largest available meta‐analysis of GWAS of migraine conducted by the International Headache Genetics Consortium (IHGC).

The UK Biobank data reflect that of individuals with 9 distinct sleep traits, which included over 237,627 cases. Data from 59,674 cases of migraine and 316,078 controls were gleaned from the IHGC GWAS.

In total, researchers found 7 sleep traits demonstrated genetic overlap with migraine, including difficulty awakening, insomnia symptoms, long sleep duration (≥ 9 hours), short sleep duration (< 7 hours) sleep duration, napping, and daytime sleepiness. No evidence for a genetic correlation between migraine and snoring and morning diurnal preference was found. The strongest genetic correlation was found with insomnia symptoms (rg = 0.29), followed by short sleep duration (rg = 0.18).

In addition, MR analyses “provided evidence for potential causal effects of difficulty awakening on risk of migraine (odds ratio [OR], 1.37; 95% CI, 1.12-1.68; P = .002), and nominal evidence that liability to insomnia symptoms increased the risk of migraine (OR, 1.09; 95% CI, 1.02-1.16; P = .02).”

However, the analyses yielded minimal evidence supporting an effect of migraine liability on sleep patterns or disturbances.

Overall, the results confirm highly pleiotropic migraine genetic loci also influence sleep traits, the researchers wrote. Because no evidence was found on a causal effect of morning diurnal preference on migraine, they hypothesized the effect of difficulty awakening on migraine may be driven by disturbances to sleep quality vs those from circadian mechanisms.

Potential pathways by which sleep quality or insomnia symptoms may influence migraine susceptibility include cortical excitability being increased by insomnia or sleep disturbances reducing pain thresholds causing dysfunction of the glymphatic system, potentially resulting in accumulation of nociceptive central nervous system waste.

The selection of relatively healthy individuals into the UK Biobank may limit generalizability of findings to less healthy populations and those of non-European ancestry, marking a limitation to the study.

“These data support a shared genetic basis between several sleep traits and migraine and support potential causal effects of difficulty awakening and insomnia symptoms on migraine risk,” the authors concluded. “Treatment of sleep disturbances may therefore be a promising clinical intervention in the management of migraine.”

Reference

Daghlas I, Vgontzas A, Guo Y, Chasman DI, Saxena R; International Headache Genetics Consortium. Habitual sleep disturbances and migraine: a Mendelian randomization study. Ann Clin Transl Neurol. Published online October 30, 2020. doi:10.1002/acn3.51228