Causal relationships between migraine and microstructural white matter: a Mendelian randomization study
Lei Zhao, Wenhui Zhao, Verneri Anttila, Ville Artto, Andrea Carmine Belin, Anna Bjornsdottir, Gyða Björnsdóttir, Dorret I. Boomsma, Sigrid Børte, Mona Ameri Chalmer, Daniel I. Chasman, Bru Cormand, Ester Cuenca-León, George Davey-Smith, Irene de Boer, Martin Dichgans, Tõnu Esko, Tobias Freilinger, Padhraig Gormley, Lyn R. Griffiths, Eija Hämäläinen, Thomas Folkmann Hansen, Aster V. E. Harder, Heidi Hautakangas, Marjo Hiekkala, Maria Gudlaug Hrafnsdottir, M. Arfan Ikram, Marjo‐Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Lisette J. A. Kogelman, Espen Saxhaug Kristoffersen, Christian Kubisch, Mitja Kurki, Tobias Kurth, Lenore J. Launer, Terho Lehtimäki, Davor Lessel, Lannie Ligthart, Sigurður H. Magnússon, Rainer Malik, Bertram Müller‐Myhsok, Carrie A. M. Northover, Dale R. Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda M. Pedersen, Nancy L. Pedersen, Matti Pirinen, Daniëlle Posthuma, Patricia Pozo‐Rosich, Alice Pressman, Olli Raitakari, Caroline Ran, Gudrun R. Sigurdardottir, Hreinn Stefánsson, Kāri Stefánsson, Ólafur Sveinsson, Gisela M. Terwindt, Thorgeir E. Thorgeirsson, Arn M. J. M. van den Maagdenberg, Cornelia M. van Duijn, Maija Wessman, Bendik S. Winsvold, John‐Anker Zwart, Jin Cao, Yiheng Tu
Abstract
Abstract 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.