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

Background: 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). Methods: 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). Results: 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. Conclusions: 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.

Migraine; Mendelian randomization; Genome-wide association study; Lipids; Lipid species; Causal effect

[1] Stovner LJ, Hagen K, Linde M, Steiner TJ. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. The Journal of Headache and Pain. 2022; 23: 34.

[2] Steiner TJ, Stovner LJ. Global epidemiology of migraine and its implications for public health and health policy. Nature Reviews Neurology. 2023; 19: 109–117.

[3] Gao F, Jiang H, Cao M, Guo X, Dong J, Wang Q, et al. Global, regional, and national burden of headache disorders, 1990–2021: a systematic analysis of the Global Burden of Disease Study 2021. Headache. 2025. PMID: 41181886.

[4] Caponnetto V, Deodato M, Robotti M, Koutsokera M, Pozzilli V, Galati C, et al. Comorbidities of primary headache disorders: a literature review with meta-analysis. The Journal of Headache and Pain. 2021; 22: 71.

[5] Buse DC, Reed ML, Fanning KM, Bostic R, Dodick DW, Schwedt TJ, et al. Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in America symptoms and treatment (MAST) study. The Journal of Headache and Pain. 2020; 21: 23.

[6] Liu H, Niu W, Ma G, Fan H, Zhang M, Wang Y, et al. Cardiovascular health status, migraine risk, and mortality outcomes in migraine individuals: insights from NHANES. Brain and Behavior. 2026; 16: e71162.

[7] Terhart M, Overeem LH, Hong JB, Reuter U, Raffaelli B. Comorbidities as risk factors for migraine onset: a systematic review and three-level meta-analysis. European Journal of Neurology. 2025; 32: e16590.

[8] Liampas I, Mylonas KS, Brotis A, Dervenis P, Siokas V, Mentis AA, et al. Serum lipid abnormalities in migraine: a meta-analysis of observational studies. Headache. 2021; 61: 44–59.

[9] Ge W, Gao L, Zhang Y, Wu K, Chen N, He L. Association between serum lipid levels and severe headache or migraine in representative American population: a cross-sectional study. Current Neurovascular Research. 2021; 18: 333–342.

[10] Onderwater GLJ, Ligthart L, Bot M, Demirkan A, Fu J, van der Kallen CJH, et al. Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine. Neurology. 2019; 92: e1899–e1911.

[11] Lu ZX, Dong BQ, Chen L, Wei HL. Association of the total cholesterol to high-density lipoprotein cholesterol ratio with all-cause mortality risk in the migraine population. The Journal of Headache and Pain. 2025; 26: 135.

[12] Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nature Reviews Immunology. 2015; 15: 104–116.

[13] Bi Y, Zhu Y, Tang S, Huang Y. Lipids, lipid-modifying drug target genes and migraine: a Mendelian randomization study. The Journal of Headache and Pain. 2023; 24: 112.

[14] Guo Y, Daghlas I, Gormley P, Giulianini F, Ridker PM, Mora S, et al. Phenotypic and genotypic associations between migraine and lipoprotein subfractions. Neurology. 2021; 97: e2223–e2235.

[15] Hong P, Han L, Wan Y. Mendelian randomization study of lipid metabolism characteristics and migraine risk. European Journal of Pain. 2024; 28: 978–986.

[16] Zhang PA, Wang JL, Dong MH, Huang XC, Li NJ, Qin RD, et al. Genetic influence of the brain imaging phenotypes, brain and cerebrospinal fluid metabolites and brain genes on migraine subtypes: a Mendelian randomization and multi-omics study. The Journal of Headache and Pain. 2025; 26: 124.

[17] Hornburg D, Wu S, Moqri M, Zhou X, Contrepois K, Bararpour N, et al. Dynamic lipidome alterations associated with human health, disease and ageing. Nature Metabolism. 2023; 5: 1578–1594.

[18] Russo AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiological Reviews. 2023; 103: 1565–1644.

[19] Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Davey Smith G, et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis. PLOS Medicine. 2020; 17: e1003062.

[20] Barton AR, Sherman MA, Mukamel RE, Loh PR. Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses. Nature Genetics. 2021; 53: 1260–1269.

[21] Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genetic Epidemiology. 2016; 40: 304–314.

[22] Li X, Liu Q, Ni H, Ni J, Yang S, Ji J. Causal factors for migraine in Mendelian randomization studies: a systematic review and meta-analysis. Frontiers in Neurology. 2025; 16: 1660995.

[23] Kalkman DN, Couturier EGM, El Bouziani A, Dahdal J, Neefs J, Woudstra J, et al. Migraine and cardiovascular disease: what cardiologists should know. European Heart Journal. 2023; 44: 2815–2828.

[24] Liu H, Zhang S, Gong Z, Zhao W, Lin X, Liu Y, et al. Association between migraine and cardiovascular disease mortality: a prospective population-based cohort study. Headache. 2023; 63: 1109–1118.

[25] Duan X, Du X, Zheng G, Zhou X, Tan N, Li G, et al. Causality between migraine and cardiovascular disease: a bidirectional Mendelian randomization study. The Journal of Headache and Pain. 2024; 25: 130.

[26] Wang K, Mao Y, Lu M, Ding Y, Li Z, Li Y, et al. Association between migraine and cardiovascular disease: a cross-sectional study. Frontiers in Cardiovascular Medicine. 2022; 9: 1044465.

[27] Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. Journal of the American College of Cardiology. 2009; 54: 2129–2138.

[28] Siewert KM, Klarin D, Damrauer SM, Chang KM, Tsao PS, Assimes TL, et al. Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache. International Journal of Epidemiology. 2020; 49: 1022–1031.

[29] Tao X, Tao R, Wang K, Wu L. Anti-inflammatory mechanism of Apolipoprotein A-I. Frontiers in Immunology. 2024; 15: 1417270.

[30] Groenen AG, Halmos B, Tall AR, Westerterp M. Cholesterol efflux pathways, inflammation, and atherosclerosis. Critical Reviews in Biochemistry and Molecular Biology. 2021; 56: 426–439.

[31] Murphy AJ, Woollard KJ. High-density lipoprotein: a potent inhibitor of inflammation. Clinical and Experimental Pharmacology and Physiology. 2010; 37: 710–718.

[32] Guo K, Hu C, Li L, Liu X, Liu Y, Zhang D, et al. ApoA1/HDL and sepsis-associated vascular endothelial injury: a narrative review. Critical Care. 2025; 29: 426.

[33] Biscetti L, De Vanna G, Cresta E, Bellotti A, Corbelli I, Letizia Cupini M, et al. Immunological findings in patients with migraine and other primary headaches: a narrative review. Clinical and Experimental Immunology. 2022; 207: 11–26.

[34] Gokce M, Bektay MY, Uzun M, Ulutas C, Uslu F, Guler EM. Cardiovascular comorbidities are risk factors for increased oxidative stress and DNA damage in migraine patients: a prospective cohort study. Journal of Translational Medicine. 2025; 23: 1068.

[35] Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. Journal of the American College of Cardiology. 2017; 69: 692–711.

[36] Lo WL, Hsu BG, Wang CH, Lin YL, Kuo CH, Lai YH. Lipoprotein(a) levels predict endothelial dysfunction in maintenance hemodialysis patients: evidence from vascular reactivity index assessment. Renal Failure. 2025; 47: 2581940.

[37] Al-Hassany L, MaassenVanDenBrink A, Kurth T. Cardiovascular risk scores and migraine status. JAMA Network Open. 2024; 7: e2440577.

[38] Cinzia F, Daniela P, Elena S, Francesco S, Emilia A, Sandra F, et al. Lipoprotein (a) [Lp(a)]: a possible link between migraine and stroke. Translational Research. 2009; 153: 44–47.

[39] Saberi A, Hatamian HR, Kazemnejad E, Ghorbannejad N. Hyperlipidemia in migraine: is it more frequent in migraineurs? Iranian Journal of Neurology. 2011; 10: 46–50.

[40] Le Quan Sang KH, Mazeaud M, Astarie C, Duranthon V, Driss F, Devynck MA. Plasma lipids and platelet membrane fluidity in essential hypertension. Thrombosis and Haemostasis. 1993; 69: 70–76.

[41] Sener A, Ozsavci D, Oba R, Demirel GY, Uras F, Yardimci KT. Do platelet apoptosis, activation, aggregation, lipid peroxidation and platelet–leukocyte aggregate formation occur simultaneously in hyperlipidemia? Clinical Biochemistry. 2005; 38: 1081–1087.

[42] van der Veen JN, Kennelly JP, Wan S, Vance JE, Vance DE, Jacobs RL. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochimica et Biophysica Acta (BBA)—Biomembranes. 2017; 1859: 1558–1572.

[43] Kwarteng DO, Gangoda M, Kooijman EE. The effect of methylated phosphatidylethanolamine derivatives on the ionization properties of signaling phosphatidic acid. Biophysical Chemistry. 2023; 296: 107005.

[44] van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nature Reviews Molecular Cell Biology. 2008; 9: 112–124.

[45] Li Q, Xia Z, Wu Y, Ma Y, Zhang D, Wang S, et al. Lysophospholipid acyltransferase-mediated formation of saturated glycerophospholipids maintained cell membrane integrity for hypoxic adaptation. The FEBS Journal. 2024; 291: 3191–3210.

[46] Lingwood D, Simons K. Lipid rafts as a membrane-organizing principle. Science. 2010; 327: 46–50.

[47] Mustonen AM, Nieminen P. Dihomo-γ-linolenic acid (20:3n-6)-metabolism, derivatives, and potential significance in chronic inflammation. International Journal of Molecular Sciences. 2023; 24: 2116s.

[48] Antonova M, Wienecke T, Olesen J, Ashina M. Prostaglandin E2 induces immediate migraine-like attack in migraine patients without aura. Cephalalgia. 2012; 32: 822–833.

[49] Schooneveldt YL, Paul S, Calkin AC, Meikle PJ. Ether lipids in obesity: from cells to population studies. Frontiers in Physiology. 2022; 13: 841278.

[50] Simons K, Ikonen E. Functional rafts in cell membranes. Nature. 1997; 387: 569–572.

[51] Hannun YA, Obeid LM. Sphingolipids and their metabolism in physiology and disease. Nature Reviews Molecular Cell Biology. 2018; 19: 175–191.

[52] Pietrobon D, Moskowitz MA. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nature Reviews Neuroscience. 2014; 15: 379–393.

[53] Newton AC. Protein kinase C: poised to signal. American Journal of Physiology-Endocrinology and Metabolism. 2010; 298: E395–E402.

[54] Calder PC. Functional roles of fatty acids and their effects on human health. Journal of Parenteral and Enteral Nutrition. 2015; 39: 18S–32S.