Exploring the Genetic Relationship Between Migraine Subtypes, Depression And Anxiety Using Polygenic Scores

Migraine is a disabling neurological disorder that frequently co-occurs with depression and anxiety. While prior research suggests a genetic association between these conditions, little is known about the genetic relationships underlying specific migraine subtypes. Bivariate genetic correlations between migraine with depression and anxiety were estimated using Linkage-Disequilibrium Score Regression (LDSC), drawing on publicly available large-scale Genome-Wide Association Study data for these traits. In addition, PGS were constructed using the same data and applied to two target cohorts for out-of-sample prediction of migraine and its subtypes. These were a depression-enriched cohort ( Australian Genetics of Depression Study ; N=12,601), and an unselected population cohort ( QSkin Study of Sun and Health ; N=16,532). Migraine subtypes were defined according to standard criteria and comprised a broad migraine without aura phenotype and three nested subtypes: migraine with aura, and chronic migraine with and without aura.

We found significant genetic correlations between migraine and depression ( r _g =0.29), as well as between migraine and anxiety ( r _g =0.32). Across both cohorts, Migraine ( OR ≈1.35) and Depression PGS ( OR ≈1.12) were significantly associated with all measures of migraine and its subtypes. Depression PGS remained significantly associated with all non-chronic migraine subtypes after controlling for migraine and anxiety PGS, suggesting an independent contribution of depression genetic risk on migraine. Anxiety PGS were significantly associated with all non-chronic migraine subtypes ( OR ≈1.09). However, these associations did not persist after adjustment for migraine and/or depression PGS. These results provide insight into the genetic relationships between migraine and its subtypes with depression and anxiety.