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

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Gene-Based Pleiotropy Across Migraine with Aura and Migraine Without Aura Gene-based pleiotropy across migraine with aura and migraine without aura Huiying Zhao1,2#, Else Eising3#, Boukje de Vries3; 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 Freilinger14,21, 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 Quaye36, Christian Kubisch37,38, Martin Dichgans14,25, Maija Wessman4,31, Kari Stefansson12,39, Daniel I 11 4,5,7,40-41 2 2 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, 1 Oslo, Norway. 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, Klinikum der Universität München, Munich, 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. 2 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. 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. 35Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 36Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK. 37Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 38Institute of Human Genetics, University of Ulm, Ulm, Germany. 39School of Medicine, University of Iceland, Reykjavik, Iceland. 40Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 41Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. #These authors contributed equally to this work. *These authors jointly directed this work. 3 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] 4 Abstract Introduction: It is unclear whether migraine with aura (MA) and migraine without aura (MO) are distinct subtypes or 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 statistics 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 (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 closely located on chromosome 12q13.13, represent novel candidate risk genes. The genes overlapping in both migraine types were enriched for functions involved in inflammation, cardiovasculature and connective tissue. 5 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 NPFF as novel candidate risk genes for both types of migraine. Keywords Migraine; aura; genome-wide; association; gene-based; pleiotropy 6 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 migraine aura is 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 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 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 7 (IHGC) identified 142 single nucleotide polymorphisms (SNPs) at 12 independent loci significantly associated with migraine (P-values < 5×10-8) (11). Many genes in or near these loci are involved in neuronal function, thus supporting a role for neuronal signaling in migraine etiology as had previously been shown for monogenic familial hemiplegic migraine, a subtype of migraine with aura (12). In addition, 1,168 SNPs at 134 loci showed suggestive association with migraine (P-values < 1×10-5) (11). When considering only the genome-wide significant hits, GWA studies have been most successful utilizing case samples satisfying criteria for only MO, with six loci identified (11, 13) compared to only one locus utilizing case samples satisfying criteria for only MA (14). The remaining five genome-wide significant loci were identified
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