Elucidating the relationship between migraine risk and brain structure using genetic data
Authors: Mitchell Brittany L , Diaz-Torres Santiago , Bivol Svetlana , Cuellar-Partida Gabriel ,   International Headache Genetics Consortium, Gormley Padhraig , Anttila Verneri , Winsvold Bendik S , Palta Priit , Esko Tonu , Pers Tune H , Farh Kai-How , Cuenca-Leon Ester , Muona Mikko , Furlotte Nicholas A , Kurth Tobias , Ingason Andres , McMahon George , Ligthart Lannie , Terwindt Gisela M , Kallela Mikko , Freilinger Tobias M , Ran Caroline , Gordon Scott G , Stam Anine H , Steinberg Stacy , Borck Guntram , Koiranen Markku , Quaye Lydia , Adams Hieab H H , Lehtimäki Terho , Sarin Antti-Pekka , Wedenoja Juho , Hinds David A , Buring Julie E , Schürks Markus , Ridker Paul M , Hrafnsdottir Maria Gudlaug , Stefansson Hreinn , Ring Susan M , Hottenga Jouke-Jan , Penninx Brenda W J H , Färkkilä Markus , Artto Ville , Kaunisto Mari , Vepsäläinen Salli , Malik Rainer , Heath Andrew C , Madden Pamela A F , Martin Nicholas G , Montgomery Grant W , Kurki Mitja , Kals Mart , Mägi Reedik , Pärn Kalle , Hämäläinen Eija , Huang Hailiang , Byrnes Andrea E , Franke Lude , Huang Jie , Stergiakouli Evie , Lee Phil H , Sandor Cynthia , Webber Caleb , Cader Zameel , Muller-Myhsok Bertram , Schreiber Stefan , Meitinger Thomas , Eriksson Johan G , Salomaa Veikko , Heikkilä Kauko , Loehrer Elizabeth , Uitterlinden Andre G , Hofman Albert , van Duijn Cornelia M , Cherkas Lynn , Pedersen Linda M , Stubhaug Audun , Nielsen Christopher S , Männikkö Minna , Mihailov Evelin , Milani Lili , Göbel Hartmut , Esserlind Ann-Louise , Christensen Anne Francke , Hansen Thomas Folkmann , Werge Thomas , Børte Sigrid , Cormand Bru , Eising Else , Griffiths Lyn , Hamalainen Eija , Hiekkala Marjo , Kajanne Risto , Launer Lenore , Lehtimaki Terho , Leslsel Davor , Macaya Alfons , Mangino Massimo , Pedersen Nancy , Posthuma Danielle , Pozo-Rosich Patricia , Pressman Alice , Sintas Celia , Vila-Pueyo Marta , Kaprio Huiying Zhao Jaakko , Aromaa Arpo J , Raitakari Olli , Ikram M Arfan , Spector Tim , Järvelin Marjo-Riitta , Metspalu Andres , Kubisch Christian , Strachan David P , Ferrari Michel D , Belin Andrea C , Dichgans Martin , Wessman Maija , van den Maagdenberg Arn M J M , Zwart John-Anker , Boomsma Dorret I , Smith George Davey , Stefansson Kari , Eriksson Nicholas , Daly Mark J , Neale Benjamin M , Olesen Jes , Chasman Daniel I , Nyholt Dale R , Palotie Aarno , Gerring Zachary F , Martin Nicholas G , Medland Sarah E , Grasby Katrina L , Nyholt Dale R , Rentería Miguel E 
Published: March 2022

Abstract
Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined.
Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach.
We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = −0.11, P = 1 × 10−3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala.
We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.