Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset

Shengjun Hong, Dmitry Prokopenko, Valerija Dobricic, Fabian Kilpert, Isabelle Bos, Stephanie J. B. Vos, Betty M. Tijms, Ulf Andreasson, Kaj Blennow, View ORCID ProfileRik Vandenberghe, Isabelle Cleynen, Silvy Gabel, Jolien Schaeverbeke, Philip Scheltens, Charlotte E. Teunissen, Ellis Niemantsverdriet, Sebastiaan Engelborghs, Giovanni Frisoni, Olivier Blin, Jill C. Richardson, Regis Bordet, José Luis Molinuevo, Lorena Rami, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Petronella Kettunen, Anders Wallin, Alberto Lleó, Isabel Sala, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Kristel Sleegers, Christine Van Broeckhoven, Mara ten Kate, View ORCID ProfileFrederik Barkhof, Henrik Zetterberg, Simon Lovestone, Johannes Streffer, Michael Wittig, View ORCID ProfileAndre Franke, Rudolph E Tanzi, Pieter Jelle Visser, View ORCID ProfileLars Bertram
doi: https://doi.org/10.1101/774554
Shengjun Hong
1Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dmitry Prokopenko
3Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Valerija Dobricic
1Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fabian Kilpert
1Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Isabelle Bos
4Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands; Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephanie J. B. Vos
4Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands; Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Betty M. Tijms
5Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ulf Andreasson
6Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
7Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kaj Blennow
6Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
7Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rik Vandenberghe
8Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium
9Neurology Service, University Hospital Leuven, Leuven, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Rik Vandenberghe
Isabelle Cleynen
10Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Silvy Gabel
8Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jolien Schaeverbeke
8Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip Scheltens
5Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charlotte E. Teunissen
11Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ellis Niemantsverdriet
12Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sebastiaan Engelborghs
12Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
13Department of Neurology and Center for Neurosciences, UZ Brussel and Vrije Universiteit Brussel (VUB), Brussels, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giovanni Frisoni
14University of Geneva, Geneva, Switzerland
15IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Olivier Blin
16AIX Marseille University, INS, Ap-hm, Marseille, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jill C. Richardson
17Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Regis Bordet
18University of Lille, Inserm, CHU Lille, Lille, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
José Luis Molinuevo
19Alzheimer’s disease and other cognitive disorders unit, Hospital Clinic I Universitari, Barcelona, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lorena Rami
19Alzheimer’s disease and other cognitive disorders unit, Hospital Clinic I Universitari, Barcelona, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Petronella Kettunen
6Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
20Department of Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anders Wallin
6Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alberto Lleó
21Memory Unit, Neurology Department. Hospital de Sant Pau, Barcelona and Centro de Investigación Biomédica en Red en enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Isabel Sala
21Memory Unit, Neurology Department. Hospital de Sant Pau, Barcelona and Centro de Investigación Biomédica en Red en enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julius Popp
22Geriatric Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Switzerland; Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gwendoline Peyratout
23University Hospital of Lausanne, Lausanne, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pablo Martinez-Lage
24Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mikel Tainta
24Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard J. B. Dobson
25Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, UK; Health Data Research UK London, University College London, 222 Euston Road, London, UK; Institute of Health Informatics, University College London, 222 Euston Road, London, UK; The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, 222 Euston Road, London, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cristina Legido-Quigley
26Steno Diabetes Center, Copenhagen, Denmark and Institute of Pharmaceutical Sciences, King’s College London, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kristel Sleegers
27Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
28Department of Biomedical Sciences, University of Antwerp, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christine Van Broeckhoven
27Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
28Department of Biomedical Sciences, University of Antwerp, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mara ten Kate
29Alzheimer Center and Department of Neurology, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, The Netherlands
30Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frederik Barkhof
31Institutes of Neurology and Healthcare Engineering, University College London, London, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Frederik Barkhof
Henrik Zetterberg
6Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
7Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
32Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, UK
33UK Dementia Research Institute at UCL, London, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Simon Lovestone
34Department of Psychiatry, University of Oxford, Oxford, UK (currently employed at Janssen-Cilag)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Johannes Streffer
35Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
36Translational Medicine Neuroscience, UCB Biopharma SPRL, Braine l’Alleud, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Wittig
37Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andre Franke
37Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andre Franke
Rudolph E Tanzi
3Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pieter Jelle Visser
5Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lars Bertram
1Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany
2Dept of Psychology, University of Oslo, Oslo, Norway
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Lars Bertram
  • For correspondence: lars.bertram@uni-luebeck.de
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures of amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

Footnotes

  • ↵‡ Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted September 23, 2019.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset
Shengjun Hong, Dmitry Prokopenko, Valerija Dobricic, Fabian Kilpert, Isabelle Bos, Stephanie J. B. Vos, Betty M. Tijms, Ulf Andreasson, Kaj Blennow, Rik Vandenberghe, Isabelle Cleynen, Silvy Gabel, Jolien Schaeverbeke, Philip Scheltens, Charlotte E. Teunissen, Ellis Niemantsverdriet, Sebastiaan Engelborghs, Giovanni Frisoni, Olivier Blin, Jill C. Richardson, Regis Bordet, José Luis Molinuevo, Lorena Rami, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Petronella Kettunen, Anders Wallin, Alberto Lleó, Isabel Sala, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Kristel Sleegers, Christine Van Broeckhoven, Mara ten Kate, Frederik Barkhof, Henrik Zetterberg, Simon Lovestone, Johannes Streffer, Michael Wittig, Andre Franke, Rudolph E Tanzi, Pieter Jelle Visser, Lars Bertram
bioRxiv 774554; doi: https://doi.org/10.1101/774554
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset
Shengjun Hong, Dmitry Prokopenko, Valerija Dobricic, Fabian Kilpert, Isabelle Bos, Stephanie J. B. Vos, Betty M. Tijms, Ulf Andreasson, Kaj Blennow, Rik Vandenberghe, Isabelle Cleynen, Silvy Gabel, Jolien Schaeverbeke, Philip Scheltens, Charlotte E. Teunissen, Ellis Niemantsverdriet, Sebastiaan Engelborghs, Giovanni Frisoni, Olivier Blin, Jill C. Richardson, Regis Bordet, José Luis Molinuevo, Lorena Rami, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Petronella Kettunen, Anders Wallin, Alberto Lleó, Isabel Sala, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Kristel Sleegers, Christine Van Broeckhoven, Mara ten Kate, Frederik Barkhof, Henrik Zetterberg, Simon Lovestone, Johannes Streffer, Michael Wittig, Andre Franke, Rudolph E Tanzi, Pieter Jelle Visser, Lars Bertram
bioRxiv 774554; doi: https://doi.org/10.1101/774554

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (3701)
  • Biochemistry (7827)
  • Bioengineering (5699)
  • Bioinformatics (21351)
  • Biophysics (10607)
  • Cancer Biology (8212)
  • Cell Biology (11981)
  • Clinical Trials (138)
  • Developmental Biology (6790)
  • Ecology (10427)
  • Epidemiology (2065)
  • Evolutionary Biology (13912)
  • Genetics (9733)
  • Genomics (13113)
  • Immunology (8176)
  • Microbiology (20077)
  • Molecular Biology (7882)
  • Neuroscience (43187)
  • Paleontology (321)
  • Pathology (1285)
  • Pharmacology and Toxicology (2269)
  • Physiology (3365)
  • Plant Biology (7259)
  • Scientific Communication and Education (1317)
  • Synthetic Biology (2012)
  • Systems Biology (5551)
  • Zoology (1135)