Causal relationships between migraine and microstructural white matter: a Mendelian randomization study
Zhao L., Zhao W., Anttila V., Artto V., Belin AC., Bjornsdottir A., Bjornsdottir G., Boomsma DI., Børte S., Chalmer MA., Chasman DI., Cormand B., Cuenca-Leon E., Davey-Smith G., de Boer I., Dichgans M., Esko T., Freilinger T., Gormley P., Griffiths LR., Hämäläinen E., Hansen TF., Harder AVE., Hautakangas H., Hiekkala M., Hrafnsdottir MG., Ikram MA., Järvelin MR., Kajanne R., Kallela M., Kaprio J., Kaunisto M., Kogelman LJA., Kristoffersen ES., Kubisch C., Kurki M., Kurth T., Launer L., Lehtimäki T., Lessel D., Ligthart L., Magnusson SH., Malik R., Müller-Myhsok B., Northover C., Nyholt DR., Olesen J., Palotie A., Palta P., Pedersen LM., Pedersen N., Pirinen M., Posthuma D., Pozo-Rosich P., Pressman A., Raitakari O., Ran C., Sigurdardottir GR., Stefansson H., Stefansson K., Sveinsson OA., Terwindt GM., Thorgeirsson TE., van den Maagdenberg AMJM., van Duijn C., Wessman M., Winsvold BS., Zwart JA., Cao J., Tu Y.
Background: Migraine is a disabling neurological disorder with the pathophysiology yet to be understood. The microstructural alteration in brain white matter (WM) has been suggested to be related to migraine in recent studies, but these evidence are observational essentially and cannot infer a causal relationship. The present study aims to reveal the causal relationship between migraine and microstructural WM using genetic data and Mendelian randomization (MR). Methods: We collected the Genome-wide association study (GWAS) summary statistics of migraine (48,975 cases / 550,381 controls) and 360 WM imaging-derived phenotypes (IDPs) (31,356 samples) that were used to measure microstructural WM. Based on instrumental variables (IVs) selected from the GWAS summary statistics, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between migraine and microstructural WM. In forward MR analysis, we inferred the causal effect of microstructural WM on migraine by reporting the odds ratio (OR) that quantified the risk change of migraine for per 1 standard deviation (SD) increase of IDPs. In reverse MR analysis, we inferred the causal effect of migraine on microstructural WM by reporting the β value that represented SDs of changes in IDPs were caused by migraine. Results: Three WM IDPs showed significant causal associations (p < 3.29 × 10− 4, Bonferroni correction) with migraine and were proved to be reliable via sensitivity analysis. The mode of anisotropy (MO) of left inferior fronto-occipital fasciculus (OR = 1.76, p = 6.46 × 10− 5) and orientation dispersion index (OD) of right posterior thalamic radiation (OR = 0.78, p = 1.86 × 10− 4) exerted significant causal effects on migraine. Migraine exerted a significant causal effect on the OD of left superior cerebellar peduncle (β = − 0.09, p = 2.78 × 10− 4). Conclusions: Our findings provided genetic evidence for the causal relationships between migraine and microstructural WM, bringing new insights into brain structure for the development and experience of migraine.