Habitual sleep disturbances and migraine: a Mendelian randomization study

Abstract

Objective: Sleep disturbances are associated with increased risk of migraine, however the extent of shared underlying biology and the direction of causal relationships between these traits is unclear. Delineating causality between sleep patterns and migraine may offer new pathophysiologic insights and inform subsequent intervention studies. Here, we used genetic approaches to test for shared genetic influences between sleep patterns and migraine, and to test whether habitual sleep patterns may be causal risk factors for migraine and vice versa.

Methods: To quantify genetic overlap, we performed genome-wide genetic correlation analyses using genome-wide association studies of nine sleep traits in the UK Biobank (n ≥ 237,627), and migraine from the International Headache Genetics Consortium (59,674 cases and 316,078 controls). We then tested for potential causal effects between sleep traits and migraine using bidirectional, two-sample Mendelian randomization.

Results: Seven sleep traits demonstrated genetic overlap with migraine, including insomnia symptoms (rg = 0.29, P < 10^-31 ) and difficulty awakening (rg = 0.11, P < 10^-4 ). Mendelian randomization analyses provided evidence for potential causal effects of difficulty awakening on risk of migraine (OR [95% CI] = 1.37 [1.12-1.68], P = 0.002), and nominal evidence that liability to insomnia symptoms increased the risk of migraine (1.09 [1.02-1.16], P = 0.02). In contrast, there was minimal evidence for an effect of migraine liability on sleep patterns or disturbances.

Interpretation: 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. Treatment of sleep disturbances may therefore be a promising clinical intervention in the management of migraine.

Figure 1

Mendelian randomization analysis pipeline. GWAS, genome‐wide association study; IHGC, international headache genetics consortium; UKB, UK Biobank

Figure 2

Forest plot of two‐sample Mendelian randomization estimates for effects of sleep phenotypes on risk of migraine (59,674 cases and 316,078 controls). Estimates were obtained using the random‐effects inverse‐variance weighted method. CI, confidence interval

Figure 3

Forest plot of two‐sample Mendelian randomization estimates for effect of genetic liability of migraine on sleep traits. Thirty‐five single nucelotide polymorphisms were used as genetic proxies for migraine liability. Estimates were obtained using the random‐effects inverse‐variance weighted method. MR estimates for binary outcomes (insomnia symptoms, long sleep duration, short sleep duration, and snoring) are reported on the log‐odds scale. CI, confidence interval