Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subfractions
Yanjun Guo, Iyas Daghlas, Padhraig Gormley, Franco Giulianini, Paul M. Ridker, Samia Mora, Tobias Kurth, Pamela M. Rist, Daniel I. Chasman
Abstract
<h3>Background and Objective</h3> To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions. <h3>Methods</h3> We evaluated phenotypic associations between migraine and 19 lipoprotein subfraction measures in the Women9s Genome Health Study (n = 22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium for migraine (n<sub>case</sub> = 54,552, n<sub>control</sub> = 297,970) and combined summary data for lipoprotein subfractions (n up to 47,713). <h3>Results</h3> 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 (<i>p</i> = 0.001) between migraine and triglyceride-rich lipoproteins (TRLPs) concentration but not for low-density lipoprotein or high-density lipoprotein 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 4 loci (<i>chr2p21</i> harboring <i>THADA</i>, <i>chr5q13.3</i> harboring <i>HMGCR</i>, <i>chr6q22.31</i> harboring <i>HEY2</i>, and <i>chr7q11.23</i> harboring <i>MLXIPL</i>) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (<i>p</i> < 0.05) in a smaller sample from the UK Biobank. The shared signal at <i>chr5q13.3</i> colocalized with expression of <i>HMGCR</i>, <i>ANKDD1B</i>, and <i>COL4A3BP</i> in multiple tissues. <h3>Conclusions</h3> The study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may help identify potential targets for future migraine therapeutics. <h3>Classification of Evidence</h3> This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.