Headache.?2023 May;63(5):642-651.?doi: 10.1111/head.14470.?Epub 2023 Jan 27. 

Nike Zoe Welander?1,?Gull Rukh?1,?Mathias Rask-Andersen?2,?Aster V E Harder?3?4;?International Headache Genetics Consortium;?Arn M J M van den Maagdenberg?3?4,?Helgi Birgir Schiöth?1,?Jessica Mwinyi?1 

Collaborators 

• International Headache Genetics Consortium:? 

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

Author information

1Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. 

2Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 

3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands. 

4Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands. 

Abstract

Objective:?To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease. 

Background:?Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition. 

Methods:?Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed. 

Results:?Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction. 

Conclusions:?We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.