title: A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach.
abstract: Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10⁻⁷), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10⁻⁸). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10⁻¹⁵; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
authors: Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom.
authors: Matthew
authors: M
authors: Traylor
authors: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; School of Medicine, University of Tampere, Tampere, Finland.
authors: Kari-Matti
authors: KM
authors: Mäkelä
authors: Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom.
authors: Laura L
authors: LL
authors: Kilarski
authors: Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
authors: Elizabeth G
authors: EG
authors: Holliday
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: William J
authors: WJ
authors: Devan
authors: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America.
authors: Mike A
authors: MA
authors: Nalls
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors: Kerri L
authors: KL
authors: Wiggins
authors: Perelman School of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Wei
authors: W
authors: Zhao
authors: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Research and Development Program, Veterans Affairs Maryland Health Care System, Baltimore, Maryland, United States of America.
authors: Yu-Ching
authors: YC
authors: Cheng
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Sefanja
authors: S
authors: Achterberg
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Rainer
authors: R
authors: Malik
authors: Division of Clinical Neurosciences and Insititute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors: Cathie
authors: C
authors: Sudlow
authors: Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors: Steve
authors: S
authors: Bevan
authors: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; School of Medicine, University of Tampere, Tampere, Finland.
authors: Emma
authors: E
authors: Raitoharju
authors: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; School of Medicine, University of Tampere, Tampere, Finland; Department of Surgery, Tampere University Hospital, Tampere, Finland.
authors: Niku
authors: N
authors: Oksala
authors: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology - Laboratory of Neurobiology, Leuven, Belgium; VIB - Vesalius Research Center, Leuven, Belgium; University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
authors: Vincent
authors: V
authors: Thijs
authors: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology - Laboratory of Neurobiology, Leuven, Belgium; VIB - Vesalius Research Center, Leuven, Belgium; University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
authors: Robin
authors: R
authors: Lemmens
authors: Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden; Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden.
authors: Arne
authors: A
authors: Lindgren
authors: Department of Neurology, Jagiellonian University, Krakow, Poland.
authors: Agnieszka
authors: A
authors: Slowik
authors: Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia; School of Nursing and Midwifery, University of Newcastle, Callaghan, New South Wales, Australia; Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, New South Wales, Australia.
authors: Jane M
authors: JM
authors: Maguire
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Matthew
authors: M
authors: Walters
authors: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Ale
authors: A
authors: Algra
authors: Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, United Kingdom.
authors: Pankaj
authors: P
authors: Sharma
authors: Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia; Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, New South Wales, Australia.
authors: John R
authors: JR
authors: Attia
authors: Department of Cereberovascular Disease, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milan, Italy.
authors: Giorgio B
authors: GB
authors: Boncoraglio
authors: Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom.
authors: Peter M
authors: PM
authors: Rothwell
authors: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Medical Genetics, University Medical Centre, Utrecht, The Netherlands; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Paul I W
authors: PI
authors: de Bakker
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors: Joshua C
authors: JC
authors: Bis
authors: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Center for Non-Communicable Diseases, Karachi, Pakistan.
authors: Danish
authors: D
authors: Saleheen
authors: Research and Development Program, Veterans Affairs Maryland Health Care System, Baltimore, Maryland, United States of America.
authors: Steven J
authors: SJ
authors: Kittner
authors: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors: Braxton D
authors: BD
authors: Mitchell
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Jonathan
authors: J
authors: Rosand
authors: Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America.
authors: James F
authors: JF
authors: Meschia
authors: Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia; Centre for Translational Neuroscience and Mental Health, University of Newcastle, Callaghan, New South Wales, Australia.
authors: Christopher
authors: C
authors: Levi
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität, Munich, Germany.
authors: Martin
authors: M
authors: Dichgans
authors: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; School of Medicine, University of Tampere, Tampere, Finland.
authors: Terho
authors: T
authors: Lehtimäki
authors: Department of Medical & Molecular Genetics, King's College London, London, United Kingdom; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.
authors: Cathryn M
authors: CM
authors: Lewis
authors: Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors: Hugh S
authors: HS
authors: Markus
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001158:Arteries / Q000473:pathology; D003324:Coronary Artery Disease / Q000145:classification / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D055106:Genome-Wide Association Study; D006025:Glycosaminoglycans / Q000235:genetics; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide
chemical_list: D006025:Glycosaminoglycans; C007858:glucuronyl glucosamine glycan sulfate; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12