Causal relationships between migraine and microstructural white matter: a Mendelian randomization study
Authors: Zhao Lei , Zhao Wenhui ,   International Headache Genetics Consortium (IHGC), Anttila Verneri , Artto Ville , Belin Andrea C. , Bjornsdottir Anna , Bjornsdottir Gyda , Boomsma Dorret I. , Børte Sigrid , Chalmer Mona A. , Chasman Daniel I. , Cormand Bru , Cuenca-Leon Ester , Davey-Smith George , de Boer Irene , Dichgans Martin , Esko Tonu , Freilinger Tobias , Gormley Padhraig , Griffiths Lyn R. , Hämäläinen Eija , Hansen Thomas F. , Harder Aster V. E. , Hautakangas Heidi , Hiekkala Marjo , Hrafnsdottir Maria G. , Ikram M. Arfan , Järvelin Marjo-Riitta , Kajanne Risto , Kallela Mikko , Kaprio Jaakko , Kaunisto Mari , Kogelman Lisette J. A. , Kristoffersen Espen S. , Kubisch Christian , Kurki Mitja , Kurth Tobias , Launer Lenore , Lehtimäki Terho , Lessel Davor , Ligthart Lannie , Magnusson Sigurdur H. , Malik Rainer , Müller-Myhsok Bertram , Northover Carrie , Nyholt Dale R. , Olesen Jes , Palotie Aarno , Palta Priit , Pedersen Linda M. , Pedersen Nancy , Pirinen Matti , Posthuma Danielle , Pozo-Rosich Patricia , Pressman Alice , Raitakari Olli , Ran Caroline , Sigurdardottir Gudrun R. , Stefansson Hreinn , Stefansson Kari , Sveinsson Olafur A. , Terwindt Gisela M. , Thorgeirsson Thorgeir E. , van den Maagdenberg Arn M. J. M. , van Duijn Cornelia , Wessman Maija , Winsvold Bendik S. , Zwart John-Anker , Cao Jin , Tu Yiheng 
Published: February 2023

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.