Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache
Authors: Siewert Katherine M , Klarin Derek , Damrauer Scott M , Chang Kyong-Mi , Tsao Philip S , Assimes Themistocles L , Davey Smith George , Voight Benjamin F ,   The 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 HH , 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 WJH , 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 , Lessel Davor , Macaya Alfons , Mangino Massimo , Pedersen Nancy , Posthuma Danielle , Pozo-Rosich Patricia , Pressman Alice , Sintas Celia , Vila-Pueyo Marta , Zhao Huiying , Kaprio 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 MJM , 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 
Published: March 2020

Abstract

Background
Nearly a fifth of the world’s population suffer from migraine headache, yet risk factors for this disease are poorly characterized.

Methods
To further elucidate these factors, we conducted a genetic correlation analysis using cross-trait linkage disequilibrium (LD) score regression between migraine headache and 47 traits from the UK Biobank. We then tested for possible causality between these phenotypes and migraine, using Mendelian randomization. In addition, we attempted replication of our findings in an independent genome-wide association study (GWAS) when available.

Results
We report multiple phenotypes with genetic correlation (P  &lt; 1.06 × 10−3) with migraine, including heart disease, type 2 diabetes, lipid levels, blood pressure, autoimmune and psychiatric phenotypes. In particular, we find evidence that blood pressure directly contributes to migraine and explains a previously suggested causal relationship between calcium and migraine.

Conclusions
This is the largest genetic correlation analysis of migraine headache to date, both in terms of migraine GWAS sample size and the number of phenotypes tested. We find that migraine has a shared genetic basis with a large number of traits, indicating pervasive pleiotropy at migraine-associated loci.