Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies

Dale R Nyholt; International Headache Genetics Consortium; Verneri Anttila; Bendik S Winsvold; Tobias Kurth; Hreinn Stefansson; Mikko Kallela; Rainer Malik; Boukje de Vries; Gisela M Terwindt; M Arfan Ikram; Anine H Stam; Lannie Ligthart; Tobias Freilinger; Michael Alexander; Bertram Muller-Myhsok; Stefan Schreiber; Thomas Meitinger; Arpo Aromaa; Johan G Eriksson; Jaakko Kaprio; Dorret I Boomsma; Cornelia van Duijn; Olli Raitakari; Marjo-Riitta Järvelin; John-Anker Zwart; Lydia Quaye; David P Strachan; Christian Kubisch; Michel D Ferrari; Arn M J M van den Maagdenberg; Martin Dichgans; Maija Wessman; George Davey Smith; Kari Stefansson; Daniel I Chasman; Aarno Palotie

doi:10.1177/0333102414547784

Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies

Cephalalgia. 2015 May;35(6):489-99. doi: 10.1177/0333102414547784. Epub 2014 Sep 1.

Authors

Dale R Nyholt¹; International Headache Genetics Consortium; Verneri Anttila², Bendik S Winsvold³, Tobias Kurth⁴, Hreinn Stefansson⁵, Mikko Kallela⁶, Rainer Malik⁷, Boukje de Vries⁸, Gisela M Terwindt⁹, M Arfan Ikram¹⁰, Anine H Stam⁹, Lannie Ligthart¹¹, Tobias Freilinger¹², Michael Alexander¹³, Bertram Muller-Myhsok¹⁴, Stefan Schreiber¹⁵, Thomas Meitinger¹⁶, Arpo Aromaa¹⁷, Johan G Eriksson¹⁸, Jaakko Kaprio¹⁹, Dorret I Boomsma²⁰, Cornelia van Duijn²¹, Olli Raitakari²², Marjo-Riitta Järvelin²³, John-Anker Zwart³, Lydia Quaye²⁴, David P Strachan²⁵, Christian Kubisch²⁶, Michel D Ferrari⁹, Arn M J M van den Maagdenberg²⁷, Martin Dichgans²⁸, Maija Wessman²⁹, George Davey Smith³⁰, Kari Stefansson³¹, Daniel I Chasman³², Aarno Palotie³³

Affiliations

¹ Neurogenetics Laboratory, QIMR Berghofer, Australia [email protected].
² Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, USA Harvard Medical School, USA Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, USA.
³ FORMI and Department of Neurology, Oslo University Hospital and University of Oslo, Norway.
⁴ Institut National de la Santé et de la Recherche Médicale (INSERM) Research Center for Epidemiology and Biostatistics (U897) - Team Neuroepidemiology, France University of Bordeaux, France Department of Medicine, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, USA.
⁵ deCODE Genetics, Iceland.
⁶ Department of Neurology, Helsinki University Central Hospital, Finland.
⁷ Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany.
⁸ Department of Human Genetics, Leiden University Medical Centre, the Netherlands.
⁹ Department of Neurology, Leiden University Medical Centre, the Netherlands.
¹⁰ Department of Epidemiology, Erasmus University Medical Centre, the Netherlands Department of Radiology, Erasmus University Medical Centre, the Netherlands Department of Neurology, Erasmus University Medical Centre, the Netherlands.
¹¹ Department of Biological Psychology, VU University, the Netherlands EMGO+ Institute for Health and Care Research, VU University Medical Centre, the Netherlands.
¹² Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany Department of Neurology, Klinikum der Universität München, Germany.
¹³ Department of Genomics, Life & Brain Center, University of Bonn, Germany Institute of Human Genetics, University of Bonn, Germany.
¹⁴ Max Planck Institute of Psychiatry, Germany Munich Cluster for Systems Neurology (SyNergy), Germany.
¹⁵ Institute of Clinical Molecular Biology, Christian Albrechts University, Germany Department of Internal Medicine I, Christian Albrechts University, Germany.
¹⁶ Institute of Human Genetics, Helmholtz Center Munich, Germany Institute of Human Genetics, Klinikum Rechts der Isar, Technische Universität München, Germany.
¹⁷ National Institute for Health and Welfare, Finland.
¹⁸ National Institute for Health and Welfare, Finland Institute of Genetics, Folkhälsan Research Center, Finland Department of General Practice, Helsinki University Central Hospital, Helsinki, Finland Vaasa Central Hospital, Finland Department of General Practice and Primary Health Care, University of Helsinki, Finland.
¹⁹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland Department of Public Health, Hjelt Institute, University of Helsinki, Finland Department of Mental Health and Alcohol Research, National Institute for Health and Welfare, Finland.
²⁰ Department of Biological Psychology, VU University, the Netherlands.
²¹ Department of Epidemiology, Erasmus University Medical Centre, the Netherlands.
²² Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku University Hospital, Finland Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Finland.
²³ Institute of Health Sciences, University of Oulu, Finland Unit of Primary Care, Oulu University Hospital, Finland Department of Children, Young People and Families, National Institute for Health and Welfare, Finland Department of Epidemiology and Biostatistics, School of Public Health, MRC-Health Protection Agency (HPA) Centre for Environment and Health, Faculty of Medicine, Imperial College, UK Biocenter Oulu, University of Oulu, Finland.
²⁴ Department of Twin Research and Genetic Epidemiology, King's College London, UK.
²⁵ Division of Population Health Sciences and Education, St George's, University of London, UK.
²⁶ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Germany Institute of Human Genetics, University of Ulm, Germany.
²⁷ Department of Human Genetics, Leiden University Medical Centre, the Netherlands Department of Neurology, Leiden University Medical Centre, the Netherlands.
²⁸ Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany Munich Cluster for Systems Neurology (SyNergy), Germany.
²⁹ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Institute of Genetics, Folkhälsan Research Center, Finland.
³⁰ Medical Research Council Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, UK.
³¹ deCODE Genetics, Iceland School of Medicine, University of Iceland, Iceland.
³² Department of Medicine, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, USA.
³³ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, USA Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, USA Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, USA Department of Neurology, Massachusetts General Hospital, USA.

PMID: 25179292
DOI: 10.1177/0333102414547784

Abstract

Background: There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls.

Methods: Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated (p < 5 × 10(-8); thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs.

Results: Significant heterogeneity of SNP effects (p het < 1.4 × 10(-3)) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genome-wide SNP effects to be in the same direction across the subgroups.

Conclusions: Any differences in common genetic risk across these subgroups are outweighed by the similarities. Meta-analysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.

Keywords: Migraine; association; genetic; genome-wide; heterogeneity; subgroups.

Publication types

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

MeSH terms

Female
Genetic Association Studies*
Genetic Predisposition to Disease
Humans
Male
Migraine Disorders / classification*
Migraine Disorders / genetics*
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding