Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Padhraig Gormley; Mitja I Kurki; Marjo Eveliina Hiekkala; Kumar Veerapen; Paavo Häppölä; Adele A Mitchell; Dennis Lal; Priit Palta; Ida Surakka; Mari Anneli Kaunisto; Eija Hämäläinen; Salli Vepsäläinen; Hannele Havanka; Hanna Harno; Matti Ilmavirta; Markku Nissilä; Erkki Säkö; Marja-Liisa Sumelahti; Jarmo Liukkonen; Matti Sillanpää; Liisa Metsähonkala; Seppo Koskinen; Terho Lehtimäki; Olli Raitakari; Minna Männikkö; Caroline Ran; Andrea Carmine Belin; Pekka Jousilahti; Verneri Anttila; Veikko Salomaa; Ville Artto; Markus Färkkilä; 23andMe Research Team; International Headache Genetics Consortium (IHGC); Heiko Runz; Mark J Daly; Benjamin M Neale; Samuli Ripatti; Mikko Kallela; Maija Wessman; Aarno Palotie

doi:10.1016/j.neuron.2018.04.014

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Neuron. 2018 May 16;98(4):743-753.e4. doi: 10.1016/j.neuron.2018.04.014. Epub 2018 May 3.

Authors

Padhraig Gormley¹, Mitja I Kurki¹, Marjo Eveliina Hiekkala², Kumar Veerapen¹, Paavo Häppölä³, Adele A Mitchell⁴, Dennis Lal⁵, Priit Palta³, Ida Surakka³, Mari Anneli Kaunisto³, Eija Hämäläinen³, Salli Vepsäläinen⁶, Hannele Havanka⁷, Hanna Harno⁸, Matti Ilmavirta⁹, Markku Nissilä¹⁰, Erkki Säkö¹¹, Marja-Liisa Sumelahti¹², Jarmo Liukkonen¹³, Matti Sillanpää¹⁴, Liisa Metsähonkala¹⁵, Seppo Koskinen¹⁶, Terho Lehtimäki¹⁷, Olli Raitakari¹⁸, Minna Männikkö¹⁹, Caroline Ran²⁰, Andrea Carmine Belin²⁰, Pekka Jousilahti¹⁶, Verneri Anttila²¹, Veikko Salomaa¹⁶, Ville Artto⁶, Markus Färkkilä⁶; 23andMe Research Team²²; International Headache Genetics Consortium (IHGC); Heiko Runz⁴, Mark J Daly²¹, Benjamin M Neale¹, Samuli Ripatti²³, Mikko Kallela⁶, Maija Wessman²⁴, Aarno Palotie²⁵

Collaborators

Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, Karen E Huber, Aaron Kleinman, Nadia K Litterman, Jennifer C McCreight, Matthew H McIntyre, Joanna L Mountain, Carrie A M Northover, Steven J Pitts, J Fah Sathirapongsasuti, Olga V Sazonova, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Vladimir Vacic, Catherine H Wilson, Verneri Anttila, Ville Artto, Andrea Carmine Belin, Dorret I Boomsma, Sigrid Børte, Daniel I Chasman, Lynn Cherkas, Anne Francke Christensen, Bru Cormand, Ester Cuenca-Leon, George Davey-Smith, Martin Dichgans, Cornelia van Duijn, Tonu Esko, Ann-Louise Esserlind, Michel D Ferrari, Rune R Frants, Tobias Freilinger, Nick Furlotte, Padhraig Gormley, Lyn Griffiths, Eija Hamalainen, Thomas Folkmann Hansen, Marjo Hiekkala, M Arfan Ikram, Andres Ingason, Marjo-Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Christian Kubisch, Mitja Kurki, Tobias Kurth, Lenore Launer, Terho Lehtimaki, Davor Lessel, Lannie Ligthart, Nadia Litterman, Arn van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Muller-Myhsok, Benjamin M Neale, Carrie Northover, Dale R Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda Pedersen, Nancy Pedersen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Lydia Quaye, Olli Raitakari, Markus Schürks, Celia Sintas, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, David Strachan, Gisela Terwindt, Marta Vila-Pueyo, Maija Wessman, Bendik S Winsvold, William Wrenthal, Huiying Zhao, John-Anker Zwart

Affiliations

¹ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁴ Merck Research Laboratories, Merck and Co., Kenilworth, NJ, USA.
⁵ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁶ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
⁷ Regional State Administrative Agency for Northern Finland, Oulu, Finland.
⁸ Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland; Division of Pain Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Finland.
⁹ Department of Neurology, Central Hospital Central Finland, Jyväskylä.
¹⁰ Terveystalo Clinical Research, Turku, Finland.
¹¹ Turku Headache Center, Turku, Finland.
¹² Terveystalo, Tampere, Finland.
¹³ Lääkärikeskus Ikioma, Mikkeli, Finland.
¹⁴ Departments of Child Neurology and General Practice, University of Turku, and Turku University Hospital, Turku, Finland.
¹⁵ Epilepsy Unit for Children and Adolescents, Helsinki University Hospital, Helsinki, Finland.
¹⁶ National Institute for Health and Welfare, Helsinki, Finland.
¹⁷ Department of Clinical Chemistry, Fimlab Laboratories, Faculty of Medicine and Life Sciences, University of Tampere, Finland.
¹⁸ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
¹⁹ Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.
²⁰ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
²¹ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
²² 23andMe, Inc., Mountain View, CA, USA.
²³ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Public Health, Faculty of Medicine, University of Helsinki, Finland.
²⁴ Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
²⁵ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. Electronic address: aarno.palotie@helsinki.fi.

Abstract

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10^-109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10^-17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine.

Keywords: GWAS; PRS; disease aggregation; familial aggregation; families; genome-wide association study; hemiplegic migraine; migraine; migraine with aura; polygenic risk score.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Female
Genetic Predisposition to Disease*
Genetic Variation*
Genome-Wide Association Study
Genotype
Humans
Male
Middle Aged
Migraine Disorders / genetics
Migraine with Aura / genetics*
Migraine without Aura / genetics*
Multifactorial Inheritance
Phenotype

Abstract

Publication types

MeSH terms

Grants and funding