title: SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.
abstract: Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aβ1-42.
authors.affiliation: Department of Psychiatry and Psychotherapy, Institute of Human Genetics, alfredo.ramirez@ukb.uni-bonn.de.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Herold
authors.affiliation: Clinical Neuroscience Unit, Department of Neurology.
authors.forename: David
authors.initials: D
authors.lastname: Ramonet
authors.affiliation: Institute of Human Genetics, Department of Genomics, Life & Brain Center.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
authors.forename: Piotr
authors.initials: P
authors.lastname: Lewczuk
authors.affiliation: Department of Psychiatry and Psychotherapy.
authors.forename: Julius
authors.initials: J
authors.lastname: Popp
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lacour
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Drichel
authors.affiliation: Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Louwersheimer
authors.affiliation: Clinical Neuroscience Unit, Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Markus P
authors.initials: MP
authors.lastname: Kummer
authors.affiliation: Department of Psychiatry, Hope Center for Neurological Disorders, School of Medicine.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Institute of Human Genetics, Department of Genomics, Life & Brain Center, Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, CH-4058, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Teunissen
authors.affiliation: Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Henne
authors.initials: H
authors.lastname: Holstege
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Department of Psychiatry, Charité, 14050, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.affiliation: Center for Clinical Epidemiology & Biostatistics, University of Pennsylvania, PA 19104, Philadelphia, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Naj
authors.affiliation: Department of Neurology, Boston University School of Medicine, MA 02118, Boston, USA, The Framingham Heart Study, MA 01702, Framingham, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chouraki
authors.affiliation: Inserm, U744, Lille 59000, France, Université Lille 2, Lille 59000, France, Institut Pasteur de Lille, Lille 59000, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Bellenguez
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Gerrish
authors.affiliation: Department of Psychiatry and Psychotherapy.
authors.forename: Reiner
authors.initials: R
authors.lastname: Heun
authors.affiliation: Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Frölich
authors.affiliation: Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, 79106, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hüll
authors.affiliation: Department of Fundamental Neurosciences, UNIL, 1005 Lausanne, Switzerland and.
authors.forename: Lara
authors.initials: L
authors.lastname: Buscemi
authors.affiliation: Institute of Human Genetics, Department of Genomics, Life & Brain Center, Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, CH-4058, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: Department of Psychiatry and Psychotherapy.
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.affiliation: Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HZ, Amsterdam, The Netherlands, Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Breteler
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Göttingen, 37075 Göttingen, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Rüther
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Göttingen, 37075 Göttingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: Department of Psychiatry, Department of Genetics, Washington University, St. Louis, MO 63110, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Psychiatry and Psychotherapy, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.affiliation: Department of Psychiatry and Psychotherapy, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: Clinical Neuroscience Unit, Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, 53127, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.affiliation: Institute of Human Genetics, Department of Genomics, Life & Brain Center.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000134:cerebrospinal fluid / Q000235:genetics*; D003071:Cognition; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000134:cerebrospinal fluid / Q000235:genetics*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000235:genetics*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000134:cerebrospinal fluid / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D009687:Nuclear Proteins; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D000068103:Serine-Arginine Splicing Factors