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PMID: 25027320 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

Human molecular genetics ·Vol. 23 ·No. 24 ·2014-12-15 ·Pages 6644-58

Ramirez A, van der Flier WM, Herold C, Ramonet D, Heilmann S, Lewczuk P, Popp J, Lacour A, Drichel D, Louwersheimer E, Kummer MP, Cruchaga C, Hoffmann P, Teunissen C, Holstege H, Kornhuber J, Peters O, Naj AC, Chouraki V, Bellenguez C, Gerrish A, International Genomics of Alzheimer's Project IGAP, Alzheimer's Disease Neuroimaging Initiative ADNI, Heun R, Frölich L, Hüll M, Buscemi L, Herms S, Kölsch H, Scheltens P, Breteler MM, Rüther E, Wiltfang J, Goate A, Jessen F, Maier W, Heneka MT, Becker T, Nöthen MM

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.

MeSH Terms
Aged Alzheimer Disease/cerebrospinal fluid,genetics,pathology Amyloid beta-Peptides/cerebrospinal fluid,genetics Apolipoprotein E4/cerebrospinal fluid,genetics Cognition Female Gene Expression Regulation Genome-Wide Association Study Humans Male Nuclear Proteins/cerebrospinal fluid,genetics Peptide Fragments/cerebrospinal fluid,genetics Phosphorylation Polymorphism, Single Nucleotide RNA-Binding Proteins/cerebrospinal fluid,genetics Serine-Arginine Splicing Factors Signal Transduction tau Proteins/cerebrospinal fluid,genetics
Chemicals
Amyloid beta-Peptides Apolipoprotein E4 Nuclear Proteins Peptide Fragments RNA-Binding Proteins amyloid beta-protein (1-42) tau Proteins Serine-Arginine Splicing Factors
Authors & Affiliations
39 authors, click to expand affiliations / ORCID
Ramirez Alfredo
Department of Psychiatry and Psychotherapy, Institute of Human Genetics, alfredo.ramirez@ukb.uni-bonn.de.
van der Flier Wiesje M
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.
Herold Christine
German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Ramonet David
Clinical Neuroscience Unit, Department of Neurology.
Heilmann Stefanie
Institute of Human Genetics, Department of Genomics, Life & Brain Center.
Lewczuk Piotr
Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
Popp Julius
Department of Psychiatry and Psychotherapy.
Lacour André
German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Drichel Dmitriy
German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Louwersheimer Eva
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.
Kummer Markus P
Clinical Neuroscience Unit, Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Cruchaga Carlos
Department of Psychiatry, Hope Center for Neurological Disorders, School of Medicine.
Hoffmann Per
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.
Teunissen Charlotte
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.
Holstege Henne
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.
Kornhuber Johannes
Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
Peters Oliver
Department of Psychiatry, Charité, 14050, Berlin, Germany.
Naj Adam C
Center for Clinical Epidemiology & Biostatistics, University of Pennsylvania, PA 19104, Philadelphia, USA.
Chouraki Vincent
Department of Neurology, Boston University School of Medicine, MA 02118, Boston, USA, The Framingham Heart Study, MA 01702, Framingham, USA.
Bellenguez Céline
Inserm, U744, Lille 59000, France, Université Lille 2, Lille 59000, France, Institut Pasteur de Lille, Lille 59000, France.
Gerrish Amy
Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK.
International Genomics of Alzheimer's Project (IGAP)
Alzheimer's Disease Neuroimaging Initiative (ADNI)
Heun Reiner
Department of Psychiatry and Psychotherapy.
Frölich Lutz
Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.
Hüll Michael
Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, 79106, Freiburg, Germany.
Buscemi Lara
Department of Fundamental Neurosciences, UNIL, 1005 Lausanne, Switzerland and.
Herms Stefan
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.
Kölsch Heike
Department of Psychiatry and Psychotherapy.
Scheltens Philip
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.
Breteler Monique M
German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Rüther Eckart
Department of Psychiatry and Psychotherapy, University of Göttingen, 37075 Göttingen, Germany.
Wiltfang Jens
Department of Psychiatry and Psychotherapy, University of Göttingen, 37075 Göttingen, Germany.
Goate Alison
Department of Psychiatry, Department of Genetics, Washington University, St. Louis, MO 63110, USA.
Jessen Frank
Department of Psychiatry and Psychotherapy, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Maier Wolfgang
Department of Psychiatry and Psychotherapy, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Heneka Michael T
Clinical Neuroscience Unit, Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Becker Tim
Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, 53127, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
Nöthen Markus M
Institute of Human Genetics, Department of Genomics, Life & Brain Center.
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/ddu372
Email
alfredo.ramirez@ukb.uni-bonn.de
Published
2014-12-15
Epub
2014-00-15
Pages
6644-58
Language
English
Region
England
NLM ID
9208958
PMCID
PMC4240204
Subset
IM
Grants
NIA NIH HHS · P30 AG010129 · United States
NIA NIH HHS · U24 AG021886 · United States
NIA NIH HHS · U01 AG032984 · United States
CIHR · Canada
NIA NIH HHS · U01 AG024904 · United States
NIA NIH HHS · K01 AG030514 · United States
External Links
PubMed source DOI: 10.1093/hmg/ddu372 PMC Full Text View journal details
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