title: Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.
abstract: Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands.
authors.forename: Else
authors.initials: E
authors.lastname: Eising
authors.affiliation: Delft Bioinformatics Lab, Department of Intelligent Systems, Delft University of Technology, 2628 CD, Delft, The Netherlands.|Division of Image Processing, Department of Radiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Sjoerd M H
authors.initials: SMH
authors.lastname: Huisman
authors.affiliation: Delft Bioinformatics Lab, Department of Intelligent Systems, Delft University of Technology, 2628 CD, Delft, The Netherlands.|Division of Image Processing, Department of Radiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mahfouz
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands.
authors.forename: Lisanne S
authors.initials: LS
authors.lastname: Vijfhuizen
authors.affiliation: Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.affiliation: FORMI and Department of Neurology, Oslo University Hospital and University of Oslo, 0424, Oslo, Norway.
authors.forename: Bendik S
authors.initials: BS
authors.lastname: Winsvold
authors.affiliation: Institute of Public Health, Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany.|Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215-1204, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kurth
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, 3015 CE, Rotterdam, The Netherlands.|Department of Radiology, Erasmus University Medical Centre, 3015 CE, Rotterdam, The Netherlands.|Department of Neurology, Erasmus University Medical Centre, 3015 CE, Rotterdam, The Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Department of Neurology and Epileptology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.|Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximillians-Universität, 81377, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Freilinger
authors.affiliation: Department of Public Health, University of Helsinki, 00014, Helsinki, Finland.|Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290, Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Department of Biological Psychology, VU University, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, UK.|Center for Life-Course Health Research and Northern Finland Cohort Center, Faculty of Medicine, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.|Biocenter Oulu, University of Oulu, Aapistie 5A, P.O. Box 5000, 90014, Oulu, Finland.|Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, 90029 OYS, P.O. Box 20, 90220, Oulu, Finland.
authors.forename: Marjo-Riitta R
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: FORMI and Department of Neurology, Oslo University Hospital and University of Oslo, 0424, Oslo, Norway.
authors.forename: John-Anker
authors.initials: JA
authors.lastname: Zwart
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Quaye
authors.affiliation: Population Health Research Institute, St George's, University of London, London, SW17 0RE, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximillians-Universität, 81377, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: Medical Research Council Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, BS8 2PS, UK.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: deCODE Genetics, 101, Reykjavik, Iceland.|School of Medicine, University of Iceland, 101, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.|Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290, Helsinki, Finland.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215-1204, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.affiliation: Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands.
authors.forename: Boukje
authors.initials: B
authors.lastname: de Vries
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Brisbane, QLD, 4059, Australia.|Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: Delft Bioinformatics Lab, Department of Intelligent Systems, Delft University of Technology, 2628 CD, Delft, The Netherlands.|Division of Image Processing, Department of Radiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Boudewijn P F
authors.initials: BPF
authors.lastname: Lelieveldt
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands. A.M.J.M.van_den_Maagdenberg@lumc.nl.|Department of Neurology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands. A.M.J.M.van_den_Maagdenberg@lumc.nl.
authors.forename: Arn M J M
authors.initials: AMJM
authors.lastname: van den Maagdenberg
authors.affiliation: Delft Bioinformatics Lab, Department of Intelligent Systems, Delft University of Technology, 2628 CD, Delft, The Netherlands. m.j.t.reinders@tudelft.nl.
authors.forename: Marcel J T
authors.initials: MJT
authors.lastname: Reinders
mesh_terms: D001271:Atlases as Topic; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D008881:Migraine Disorders / Q000235:genetics / Q000503:physiopathology*