Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine

Gerrit L. J. Onderwater, Lannie Ligthart, Mariska Bot, Ayse Demirkan, Jingyuan Fu, Carla J. H. van der Kallen, Lisanne S. Vijfhuizen, Rene Pool, Jun Liu, Floris H. M. Vanmolkot, Marian Beekman, Ke-xin Wen, Najaf Amin, Carisha S. Thesing, Judith A. Pijpers, Dennis A. Kies, Ronald Zielman, Irene de Boer, Marleen M. J. van Greevenbroek, Ilja C. W. ArtsYuri Milaneschi, Miranda T. Schram, Pieter C. Dagnelie, Lude Franke, M. Arfan Ikram, Michel D. Ferrari, Jelle J. Goeman, P. Eline Slagboom, Cisca Wijmenga, Coen D. A. Stehouwer, Dorret I. Boomsma, Cornelia M. van Duijn, Brenda W. Penninx, Peter A. C. 't Hoen, Gisela M. Terwindt, Arn M. J. M. van den Maagdenberg*, BBMRI Metabolomics Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review



To identify a plasma metabolomic biomarker signature for migraine.


Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a H-1-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses.


Decreases in the level of apolipoprotein A1 (beta -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (beta -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (beta -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status.


Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

Original languageEnglish
Pages (from-to)E1899-E1911
Number of pages13
Issue number16
Publication statusPublished - 16 Apr 2019




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