Decoding the lipid-migraine link: a genetic and lipidomic investigation of migraine subtypes

Migraine frequently co-occurs with cardiovascular and metabolic diseases. Observational studies examining the association between conventional lipid profiles and migraine risk have yielded inconsistent results and cannot establish causality. This study aimed to investigate the causal effects of specific lipid species on migraine and its primary subtypes: migraine with aura (MA) and without aura (MO).

Using a Mendelian randomization (MR) methodology, this study analyzed genome-wide association study (GWAS) data from the UK Biobank and FinnGen Consortium. Exposures comprised seven lipids and 179 lipid species while the outcomes were overall migraine and its subtypes. Pleiotropy and heterogeneity were assessed using sensitivity analyses such as MR-Egger, weighted median, and Pleiotropy Residual Sum and Outlier (MR-PRESSO).

Genetically predicted higher levels of high-density lipoprotein cholesterol (HDL-C; odds ratio (OR) = 0.88; 95% confidence interval (CI), 0.82-0.93) and apolipoprotein A1 (ApoA1, OR = 0.89; 95% CI, 0.84-0.95) were associated with a reduced risk of migraine. Conversely, higher triglycerides (TG) increased the risk of overall migraine. Lipidomic analysis revealed 15 specific lipid species causally associated with overall migraine. Subtype-specific analyses revealed divergent causal profiles for MO and MA. Seven triacylglycerol (TAG) species were specifically associated with an increased risk of MO, whereas only sphingomyelins (SM) (d36:1) was linked to an increased risk of MA.

This study provides robust evidence for a causal relationship between lipid metabolism and migraine, demonstrating that these effects are highly specific to individual lipid molecules and migraine subtypes. These findings enhance our understanding of the lipid-mediated mechanisms in migraine pathogenesis and highlight potential subtype-specific pathways for developing future therapeutic and preventive strategies.