title: Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease.
abstract: Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Schulte
authors.affiliation: Department of Biochemistry, Adolf-Butenandt-Institut, Ludwig-Maximilians Universität München, Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Akio
authors.initials: A
authors.lastname: Fukumori
authors.affiliation: Paracelsus Elena Klinik, Kassel, Germany.|Neurochirurgische Klinik, Georg August Universität Göttingen, Göttingen, Germany.
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.affiliation: Genomics and Disease Group, Centre for Genomic Regulation (CRG), Pompeu Fabra University (UPF) and Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública, Barcelona, Spain.
authors.forename: Hyun
authors.initials: H
authors.lastname: Hor
authors.affiliation: Institut für Neuropathologie, Ludwig-Maximillians Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arzberger
authors.affiliation: Psychiatrische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Perneczky
authors.affiliation: Psychiatrische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurz
authors.affiliation: Psychiatrische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Diehl-Schmid
authors.affiliation: Psychiatrische Universitätsklinik, Albert Ludwigs Universität, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hüll
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.|Institut für Humangenetik, Technische Universität München, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Eckstein
authors.affiliation: Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimprich
authors.affiliation: Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Haubenberger
authors.affiliation: Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Pirker
authors.affiliation: Neurologische Klinik, Wilhelminenspital, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brücke
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bereznai
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Molnar
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.|Department of Neurology, Clinica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.|CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Lorenzo-Betancor
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.|Department of Neurology, Clinica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.|CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.
authors.forename: Pau
authors.identifier: http://orcid.org/0000-0002-7493-8777
authors.initials: P
authors.lastname: Pastor
authors.affiliation: Institut für Epidemiologie II, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institut für Genetische Epidemiologie, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Genomics and Disease Group, Centre for Genomic Regulation (CRG), Pompeu Fabra University (UPF) and Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.|Institut für Humangenetik, Technische Universität München, Munich, Germany.|Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institut für Neuropathologie, Ludwig-Maximillians Universität München, Munich, Germany.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.affiliation: Paracelsus Elena Klinik, Kassel, Germany.|Neurochirurgische Klinik, Georg August Universität Göttingen, Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trenkwalder
authors.affiliation: Department of Biochemistry, Adolf-Butenandt-Institut, Ludwig-Maximilians Universität München, Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.|Institut für Humangenetik, Technische Universität München, Munich, Germany.|Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D003704:Dementia / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D019636:Neurodegenerative Diseases / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*
chemical_list: D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins