Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subtractions

Background and Objective: To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions. Methods: We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women’s Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (N case =54,552, N control =297,970) and combined summary data for lipoprotein subfractions (N up to 47,713). Results: There was a significant phenotypic association (odds ratio=1.27 [95% confidence interval:1.12-1.44]) and a significant genetic correlation at 0.18 ( P =0.001) between migraine and triglyceride-rich lipoproteins (TRLP) concentration but not for LDL or HDL subfractions. Mendelian randomization (MR) estimates were largely null implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis revealing significant shared signals at four loci ( chr2p21 harboring THADA , chr5q13.3 harboring HMGCR , chr6q22.31 harboring HEY2 , and chr7q11.23 harboring MLXIPL ) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine ( P <0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues. Conclusions: The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics. Classification of Evidence: This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.