Multi-omics profiling of migraine links plasma proteomic signatures with lipid metabolomic measures

Migraine is a highly prevalent neurological disorder with incompletely understood molecular mechanisms. We aimed to identify migraine-associated plasma proteins and lipid metabolomic measures and to investigate their relationships through an integrated multi-omics framework. This study included 473,276 UK Biobank participants with plasma metabolomic data, of whom 50,888 also had plasma proteomic data. We evaluated 2,911 plasma proteins and 143 lipid metabolomic measures. Associations with prevalent and incident migraine were assessed using multivariable logistic regression and Cox proportional hazards models, respectively. Plasma proteins measured in both cohorts and molecular features classified as triglycerides (TG) were further evaluated in an independent Chinese validation cohort of 406 participants. Functional enrichment analysis was performed to characterize biological pathways involving migraine-associated proteins. Joint stratification analysis assessed the combined associations of lipid concentrations and relative proportions with migraine. Finally, correlation and mediation analyses were conducted to evaluate multi-omics links between migraine-associated proteins and lipid proportions. We identified ten plasma proteins consistently associated with both prevalent and incident migraine, with functional enrichment analysis of prevalent migraine-associated proteins highlighting lipid- and lipoprotein-related pathways. Subsequent lipid metabolomic analyses showed predominantly inverse associations of migraine with high-density lipoprotein (HDL) particle measures, but positive associations with total triglyceride concentration and proportion of TG in total HDL lipids. Joint stratification analyses indicated different associations between HDL particle concentration and migraine across HDL lipid proportions. Multi-omics integration identified significant mediation effects involving AMBP, IL18R1, and CDHR5 in the associations between HDL lipid proportions and migraine. This multi-omics study identifies coordinated plasma proteomic and metabolomic alterations associated with prevalent and incident migraine, providing new insights into the systemic molecular features of the disorder and the cross-omics relationships among these features.