April 2021; 7 (2) ArticleOpen Access
Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes
Isabel Alfradique-Dunham, Rami Al-Ouran, Rainer von Coelln, Cornelis Blauwendraat, Emily Hill, Lan Luo, Amanda Stillwell, Emily Young, Anita Kaw, Manuela Tan, Calwing Liao, Dena Hernandez, View ORCID ProfileLasse Pihlstrom, Donald Grosset, Lisa M. Shulman, Zhandong Liu, Guy A. Rouleau, Mike Nalls, Andrew B. Singleton, Huw Morris, Joseph Jankovic, Joshua M. Shulman
First published January 28, 2021, DOI: https://doi.org/10.1212/NXG.0000000000000557
Isabel Alfradique-Dunham
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Rami Al-Ouran
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Rainer von Coelln
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Cornelis Blauwendraat
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Emily Hill
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Lan Luo
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Amanda Stillwell
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Emily Young
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Anita Kaw
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Manuela Tan
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Calwing Liao
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Dena Hernandez
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Lasse Pihlstrom
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Donald Grosset
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Lisa M. Shulman
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Zhandong Liu
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Guy A. Rouleau
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Mike Nalls
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Andrew B. Singleton
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Huw Morris
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Joseph Jankovic
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Joshua M. Shulman
From the Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.
Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes
Isabel Alfradique-Dunham, Rami Al-Ouran, Rainer von Coelln, Cornelis Blauwendraat, Emily Hill, Lan Luo, Amanda Stillwell, Emily Young, Anita Kaw, Manuela Tan, Calwing Liao, Dena Hernandez, Lasse Pihlstrom, Donald Grosset, Lisa M. Shulman, Zhandong Liu, Guy A. Rouleau, Mike Nalls, Andrew B. Singleton, Huw Morris, Joseph Jankovic, Joshua M. Shulman
Neurol Genet Apr 2021, 7 (2) e557; DOI: 10.1212/NXG.0000000000000557
Citation Manager Formats
Make Comment
See Comments
Downloads
1205
Abstract
Objective To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.
Methods In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.
Results Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = −0.04, 95% confidence interval = −0.07–0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6 × 10−7), which harbors an independent risk allele for essential tremor.
Conclusions Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.
Glossary
- BCM=
- Baylor College of Medicine;
- ET=
- essential tremor;
- GRS=
- genetic risk score;
- GWAS=
- genome-wide association study;
- IPDGC=
- International Parkinson's Disease Genomics Consortium;
- MAF=
- minor allele frequency;
- MDS-UPDRS=
- Movement Disorder Society revised UPDRS version;
- PD=
- Parkinson disease;
- PIGD=
- postural instability/gait difficulty;
- TD=
- tremor dominant;
- UPDRS=
- Unified Parkinson's Disease Rating Scale
Footnotes
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
↵* These authors contributed equally and are co–first authors.
International Parkinson's Disease Genomics Consortium coinvestigators are listed in the appendix 2 at the end of the article.
The Article Processing Charge was funded by Huffington Foundation.
- Received June 26, 2020.
- Accepted in final form December 14, 2020.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Letters: Rapid online correspondence
No comments have been published for this article.
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Advertisement
Related Articles
- No related articles found.
Topics Discussed
Alert Me
Recommended articles
-
Article
Baseline motor findings and Parkinson disease prognostic subtypesAli H. Rajput, Michele L. Rajput, Leslie W. Ferguson et al.Neurology, June 07, 2017 -
Article
Gray matter atrophy distinguishes between Parkinson disease motor subtypesKeren Rosenberg-Katz, Talia Herman, Yael Jacob et al.Neurology, March 20, 2013 -
Article
Association of metabolic syndrome and change in Unified Parkinson's Disease Rating Scale scoresMaureen Leehey, Sheng Luo, Saloni Sharma et al.Neurology, September 29, 2017 -
Article
Association of GBA Genotype With Motor and Functional Decline in Patients With Newly Diagnosed Parkinson DiseaseJodi Maple-Grødem, Ingvild Dalen, Ole-Bjørn Tysnes et al.Neurology, December 21, 2020