Plasma metabolomic signatures of migraine in 479,760 adults

Migraine has been linked to metabolic and vascular factors, and previous metabolomic studies have implicated HDL-related alterations, but large-scale prospective evidence remains limited. We analyzed 251 baseline plasma metabolites measured by nuclear magnetic resonance in 479,760 UK Biobank participants, including 6,724 incident hospital-diagnosed migraine cases during follow-up. Prospective and cross-sectional analyses replicated and extended a coherent lipid and lipoprotein pattern: HDL-related measures were generally inversely associated with hospital-diagnosed migraine, whereas triglyceride-rich and VLDL-related measures showed positive associations. Repeated least absolute shrinkage and selection operator (LASSO) analysis prioritized 12 metabolite features, which were further examined in exploratory analyses of brain structural imaging phenotypes, migraine polygenic risk, and affective and sleep-related traits. These findings provide large-scale prospective evidence supporting a structured plasma metabolomic profile associated with hospital-diagnosed migraine and contextualize systemic lipid and lipoprotein metabolism as a relevant domain for future mechanistic and translational studies of migraine-related metabolic variation.