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

Alfredo Ramirez; Wiesje M van der Flier; Christine Herold; David Ramonet; Stefanie Heilmann; Piotr Lewczuk; Julius Popp; André Lacour; Dmitriy Drichel; Eva Louwersheimer; Markus P Kummer; Carlos Cruchaga; Per Hoffmann; Charlotte Teunissen; Henne Holstege; Johannes Kornhuber; Oliver Peters; Adam C Naj; Vincent Chouraki; Céline Bellenguez; Amy Gerrish; International Genomics of Alzheimer's Project (IGAP); Alzheimer's Disease Neuroimaging Initiative (ADNI); Reiner Heun; Lutz Frölich; Michael Hüll; Lara Buscemi; Stefan Herms; Heike Kölsch; Philip Scheltens; Monique M Breteler; Eckart Rüther; Jens Wiltfang; Alison Goate; Frank Jessen; Wolfgang Maier; Michael T Heneka; Tim Becker; Markus M Nöthen

doi:10.1093/hmg/ddu372

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

Hum Mol Genet. 2014 Dec 15;23(24):6644-58. doi: 10.1093/hmg/ddu372. Epub 2014 Jul 15.

Authors

Alfredo Ramirez¹, Wiesje M van der Flier², Christine Herold³, David Ramonet⁴, Stefanie Heilmann⁵, Piotr Lewczuk⁶, Julius Popp⁷, André Lacour³, Dmitriy Drichel³, Eva Louwersheimer², Markus P Kummer⁸, Carlos Cruchaga⁹, Per Hoffmann¹⁰, Charlotte Teunissen², Henne Holstege², Johannes Kornhuber⁶, Oliver Peters¹¹, Adam C Naj¹², Vincent Chouraki¹³, Céline Bellenguez¹⁴, Amy Gerrish¹⁵; International Genomics of Alzheimer's Project (IGAP); Alzheimer's Disease Neuroimaging Initiative (ADNI); Reiner Heun⁷, Lutz Frölich¹⁶, Michael Hüll¹⁷, Lara Buscemi¹⁸, Stefan Herms¹⁰, Heike Kölsch⁷, Philip Scheltens², Monique M Breteler³, Eckart Rüther¹⁹, Jens Wiltfang¹⁹, Alison Goate²⁰, Frank Jessen²¹, Wolfgang Maier²¹, Michael T Heneka⁸, Tim Becker²², Markus M Nöthen⁵

Affiliations

¹ Department of Psychiatry and Psychotherapy, Institute of Human Genetics, alfredo.ramirez@ukb.uni-bonn.de.
² 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.
³ German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
⁴ Clinical Neuroscience Unit, Department of Neurology.
⁵ Institute of Human Genetics, Department of Genomics, Life & Brain Center.
⁶ Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
⁷ Department of Psychiatry and Psychotherapy.
⁸ Clinical Neuroscience Unit, Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
⁹ Department of Psychiatry, Hope Center for Neurological Disorders, School of Medicine.
¹⁰ 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.
¹¹ Department of Psychiatry, Charité, 14050, Berlin, Germany.
¹² Center for Clinical Epidemiology & Biostatistics, University of Pennsylvania, PA 19104, Philadelphia, USA.
¹³ Department of Neurology, Boston University School of Medicine, MA 02118, Boston, USA, The Framingham Heart Study, MA 01702, Framingham, USA.
¹⁴ Inserm, U744, Lille 59000, France, Université Lille 2, Lille 59000, France, Institut Pasteur de Lille, Lille 59000, France.
¹⁵ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, UK.
¹⁶ Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.
¹⁷ Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, 79106, Freiburg, Germany.
¹⁸ Department of Fundamental Neurosciences, UNIL, 1005 Lausanne, Switzerland and.
¹⁹ Department of Psychiatry and Psychotherapy, University of Göttingen, 37075 Göttingen, Germany.
²⁰ Department of Psychiatry, Department of Genetics, Washington University, St. Louis, MO 63110, USA.
²¹ Department of Psychiatry and Psychotherapy, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
²² Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, 53127, Bonn, Germany, German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Alzheimer Disease / cerebrospinal fluid
Alzheimer Disease / genetics*
Alzheimer Disease / pathology
Amyloid beta-Peptides / cerebrospinal fluid
Amyloid beta-Peptides / genetics*
Apolipoprotein E4 / cerebrospinal fluid
Apolipoprotein E4 / genetics*
Cognition
Female
Gene Expression Regulation
Genome-Wide Association Study
Humans
Male
Nuclear Proteins / cerebrospinal fluid
Nuclear Proteins / genetics*
Peptide Fragments / cerebrospinal fluid
Peptide Fragments / genetics*
Phosphorylation
Polymorphism, Single Nucleotide*
RNA-Binding Proteins / cerebrospinal fluid
RNA-Binding Proteins / genetics*
Serine-Arginine Splicing Factors
Signal Transduction
tau Proteins / cerebrospinal fluid
tau Proteins / genetics*

Substances

Amyloid beta-Peptides
Apolipoprotein E4
Nuclear Proteins
Peptide Fragments
RNA-Binding Proteins
amyloid beta-protein (1-42)
tau Proteins
Serine-Arginine Splicing Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding