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Gene-Based Pleiotropy Across Migraine with Aura and Migraine Without Aura Patient Groups

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Gene-Based Pleiotropy Across Migraine with Aura and Migraine Without Aura Patient Groups Gene-based pleiotropy across migraine with aura and migraine without aura patient groups Huiying Zhao1,2#, Else Eising3#, Boukje de Vries3, Lisanne S Vijfhuizen3; for the International Headache Genetics Consortium: Verneri Anttila4–7, Bendik S Winsvold8, Tobias Kurth9–11, Hreinn Stefansson12, Mikko Kallela13, Rainer Malik14, Anine H Stam15, M Arfan Ikram16–18, Lannie Ligthart19,20, Tobias Freilinger21,14, Michael Alexander22,23, Bertram Muller-Myhsok24,25, Stefan Schreiber26,27, Thomas Meitinger28,29, Arpo Aromaa30, Johan G Eriksson30–34, Dorret I Boomsma19, Cornelia M van Duijn16, John-Anker Zwart8, Lydia Quaye35, Christian Kubisch36, Martin Dichgans14,25, Maija Wessman4,31, Kari Stefansson12,37, 11 4,5,7,38-40 2 2 Daniel I Chasman and Aarno Palotie ; Nicholas G Martin , Grant W Montgomery , , Michel D Ferrari15, Gisela M Terwindt15, Arn M J M van den Maagdenberg3,15* and Dale R Nyholt1,2* 1Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia 2QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 3Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands. 4Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. 5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 6Harvard Medical School, Boston, MA, USA. 7Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA 8FORMI and Department of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway. 1 9Institut National de la Santé et de la Recherche Médicale (INSERM) Research Center for Epidemiology and Biostatistics (U897) - Team Neuroepidemiology, Bordeaux, France. 10University of Bordeaux, Bordeaux, France. 11Department of Medicine, Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 12deCODE Genetics, Reykjavik, Iceland. 13Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. 14Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig- Maximilians-Universität, Munich, Germany. 15Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands. 16Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands. 17Department of Radiology, Erasmus University Medical Centre, Rotterdam, The Netherlands. 18Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands. 19Department of Biological Psychology, VU University, Amsterdam, The Netherlands. 20EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands. 21Department of Neurology and Epileptology and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Germany. 22Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. 23Institute of Human Genetics, University of Bonn, Bonn, Germany. 24Max Planck Institute of Psychiatry, Munich, Germany. 25Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 26Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany. 27Department of Internal Medicine I, Christian Albrechts University, Kiel, Germany. 28Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany. 2 29Institute of Human Genetics, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. 30National Institute for Health and Welfare, Helsinki, Finland. 31Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland. 32Department of General Practice, Helsinki University Central Hospital, Helsinki, Finland. 33Vaasa Central Hospital, Vaasa, Finland. 34Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. 35Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK. 36Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 37School of Medicine, University of Iceland, Reykjavik, Iceland. 38Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 39Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 40Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. #These authors contributed equally to this work. *These authors jointly directed this work. Corresponding author: Dale R Nyholt, Institute of Health and Biomedical Innovation, Queensland University of Technology, GPO Box 2434, Brisbane QLD 4001, Australia. Telephone: +61 7 31386000. Email: [email protected] 3 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 with both MA and MO. Methods: Gene-based tests were performed utilizing genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4,505 MA cases with 34,813 controls and 4,038 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 1,514 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 -3 significant evidence of gene-based overlap (pleiotropy) (Pbinomial-test = 1.6×10 ). 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. 4 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; aura; genome-wide; association; gene-based; pleiotropy 5 Introduction Two common forms of migraine exist that are clinically distinguished by the presence of aura symptoms prior to the headache phase and hence are called migraine with aura (MA) and migraine without aura (MO) (1). The International Classification of Headache Disorders (ICHD) specifies MO patients have only migraine attacks without aura, whereas MA patients are characterized by their migraine attacks with aura, but can also have attacks without aura (1). The migraine aura is likely caused by cortical spreading depression (CSD), a slowly self- propagating wave of neuronal and glial depolarization in the cortex (2). The headache is caused by activation of the trigeminovascular system, which leads to abnormal processing of pain signals in the brain stem and subsequent activation of higher order brain centres giving the sensation of pain (3). CSD has been shown to activate this pain pathway in experimental animal studies, although such proof is essentially lacking in patients (4). Whereas the biological mechanisms in the early phase of an attack seem to differ between MA and MO, they may be similar in the headache phase. Supportive evidence for converging headache generating mechanisms in both migraine types comes from the fact that some drugs have equal efficacy in treating both types of migraines (5). Moreover, several studies have reported that MA and MO frequently coexist within the same family (6, 7). A large population-based study has reported high co-occurrence of MA and MO, and found that 13% of patients with active migraine (at least one migraine attack in the past year) have both MA and MO, which is higher than expected from their individual prevalence (8). Thus, the frequent co-occurrence of the two disorders within families and individuals suggest MA and MO share―at least to some extent―the same biological mechanisms. In support of this idea, latent class and genetic analysis of migraine symptom 6 data in large Australian (9) and Dutch (10) twin samples indicated the existence of a continuum of severity, with MA being more severe but not etiologically distinct from MO. Genetics studies are starting to discover genes and loci associated with migraine. A recent genome-wide association (GWA) meta-analysis of 23,285 migraine cases and 95,425 controls of European ancestry that was conducted by the International Headache Genetics Consortium (IHGC) identified 12 independent single nucleotide polymorphism (SNP) loci (rs2651899, rs10915437, rs12134493, rs2274316, rs7577262, rs6790925, rs9349379, rs13208321, rs4379368, rs10504861, rs6478241, rs11172113) significantly associated with migraine (P- values < 5×10-8) (11). Many
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