Gene-based pleiotropy across migraine with aura and migraine without aura patient groups

Huiying Zhao; Else Eising; Boukje de Vries; Lisanne S Vijfhuizen; International Headache Genetics Consortium; Verneri Anttila; Bendik S Winsvold; Tobias Kurth; Hreinn Stefansson; Mikko Kallela; Rainer Malik; Anine H Stam; M Arfan Ikram; Lannie Ligthart; Tobias Freilinger; Michael Alexander; Bertram Müller-Myhsok; Stefan Schreiber; Thomas Meitinger; Arpo Aromas; Johan G Eriksson; Dorret I Boomsma; Cornelia M van Duijn; John-Anker Zwart; Lydia Quaye; Christian Kubisch; Martin Dichgans; Maija Wessman; Kari Stefansson; Daniel I Chasman; Aarno Palotie; Nicholas G Martin; Grant W Montgomery; Michel D Ferrari; Gisela M Terwindt; Arn M J M van den Maagdenberg; Dale R Nyholt

doi:10.1177/0333102415591497

Gene-based pleiotropy across migraine with aura and migraine without aura patient groups

Cephalalgia. 2016 Jun;36(7):648-57. doi: 10.1177/0333102415591497. Epub 2015 Dec 8.

Authors

Huiying Zhao¹, Else Eising², Boukje de Vries², Lisanne S Vijfhuizen²; International Headache Genetics Consortium; Verneri Anttila³, Bendik S Winsvold⁴, Tobias Kurth⁵, Hreinn Stefansson⁶, Mikko Kallela⁷, Rainer Malik⁸, Anine H Stam⁹, M Arfan Ikram¹⁰, Lannie Ligthart¹¹, Tobias Freilinger¹², Michael Alexander¹³, Bertram Müller-Myhsok¹⁴, Stefan Schreiber¹⁵, Thomas Meitinger¹⁶, Arpo Aromas¹⁷, Johan G Eriksson¹⁸, Dorret I Boomsma¹⁹, Cornelia M van Duijn²⁰, John-Anker Zwart⁴, Lydia Quaye²¹, Christian Kubisch²², Martin Dichgans²³, Maija Wessman²⁴, Kari Stefansson²⁵, Daniel I Chasman²⁶, Aarno Palotie²⁷, Nicholas G Martin²⁸, Grant W Montgomery²⁸, Michel D Ferrari⁹, Gisela M Terwindt⁹, Arn M J M van den Maagdenberg²⁹, Dale R Nyholt³⁰

Affiliations

¹ Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia QIMR Berghofer Medical Research Institute, Brisbane, Australia.
² Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
³ 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.
⁴ FORMI and Department of Neurology, Oslo University Hospital and University of Oslo, Norway.
⁵ 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.
⁶ deCODE Genetics, Iceland.
⁷ Department of Neurology, Helsinki University Central Hospital, Finland.
⁸ Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany.
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 and Epileptology and Hertie-Institute for Clinical Brain Research, University of Tuebingen, 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, Finland Vaasa Central Hospital, Finland Department of General Practice and Primary Health Care, University of Helsinki, Finland.
¹⁹ Department of Biological Psychology, VU University, The Netherlands.
²⁰ Department of Epidemiology, Erasmus University Medical Centre, The Netherlands.
²¹ Department of Twin Research and Genetic Epidemiology, King's College London, UK.
²² Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Germany.
²³ Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Germany Munich Cluster for Systems Neurology (SyNergy), Germany.
²⁴ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Institute of Genetics, Folkhälsan Research Center, Finland.
²⁵ deCODE Genetics, Iceland School of Medicine, University of Iceland, Iceland.
²⁶ Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia.
²⁷ 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.
²⁸ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²⁹ Department of Human Genetics, Leiden University Medical Centre, The Netherlands Department of Neurology, Leiden University Medical Centre, The Netherlands.
³⁰ Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia QIMR Berghofer Medical Research Institute, Brisbane, Australia [email protected].

Abstract

Introduction: It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related.

Aim: Using a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO.

Methods: Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO.

Results: We found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value (pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) (pbinomial-test = 1.5 × 10(-4)). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue.

Conclusions: Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both types of migraine.

Keywords: Migraine; association; aura; gene-based; genome-wide; pleiotropy.

MeSH terms

Adult
Female
Genetic Pleiotropy / genetics*
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Migraine with Aura / genetics*
Migraine without Aura / genetics*
Receptors, Neuropeptide / genetics*

Substances

Receptors, Neuropeptide
neuropeptide FF receptor

Abstract

MeSH terms

Substances

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