Mediators of the association between depression and migraine: a mendelian randomization study

An association between depression and migraine has been reported in observational studies; however, conventional observational studies are prone to bias. This study aims to investigate the causal relationship between depression and migraine and to quantify the mediating effects of known risk factors.

We applied two-sample Mendelian randomization and utilized single nucleotide polymorphisms as genetic instruments for exposure (depression) and mediators (sleep traits). We utilized summary data on genome-wide association studies for depression, sleep-related traits mediators and migraine. For depression, genome-wide association studies (depression) were utilized as a test cohort for the primary analysis. Moreover, genome-wide association studies (major depressive disorder) were utilized to test the stability of the results for the validation cohort. IVW and MR-Egger regression were applied to test the heterogeneity, and Cochran's Q statistics were calculated to quantitatively evaluate the heterogeneity. MR-PRESSO analyses were utilized to examine and correct possible horizontal pleiotropy through removing outliers, and leave-one-out analyses were utilized to identify outlier SNPs.

Genetically predicted depression was associated with migraine (OR = 1.321, 95% CI: 1.184-1.473, p < 0.001). Furthermore, risk factors insomnia was associated with migraine risk (OR = 1.766, 95% CI: 1.120-2.784, p = 0.014). The mediator insomnia accounted for 19.5% of the total effect of depression on migraine.

These results support a potential causal effect of depression on migraine, partly mediated by insomnia. Therefore, the enhancement of sleep quality and difficulty in falling asleep may reduce the migraine burden occasioned by depression.