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 derived from quantifications of five separate 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.

Details

Title
Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset
Author
Hong Shengjun 1 ; Prokopenko Dmitry 2 ; Valerija, Dobricic 1 ; Kilpert Fabian 1 ; Bos, Isabelle 3 ; Vos Stephanie J B 4 ; Tijms, Betty M 5   VIAFID ORCID Logo  ; Andreasson Ulf 6 ; Blennow Kaj 6   VIAFID ORCID Logo  ; Vandenberghe Rik 7 ; Cleynen Isabelle 8 ; Gabel Silvy 9 ; Schaeverbeke Jolien 9 ; Scheltens, Philip 5   VIAFID ORCID Logo  ; Teunissen, Charlotte E 10 ; Ellis, Niemantsverdriet 11 ; Engelborghs Sebastiaan 12   VIAFID ORCID Logo  ; Frisoni Giovanni 13 ; Blin Olivier 14 ; Richardson, Jill C 15 ; Bordet Regis 16 ; Molinuevo José Luis 17 ; Rami Lorena 17 ; Kettunen Petronella 18   VIAFID ORCID Logo  ; Wallin, Anders 19   VIAFID ORCID Logo  ; Lleó Alberto 20 ; Sala, Isabel 20 ; Popp, Julius 21 ; Peyratout Gwendoline 22 ; Martinez-Lage, Pablo 23 ; Tainta Mikel 23 ; Dobson Richard J B 24   VIAFID ORCID Logo  ; Legido-Quigley, Cristina 25 ; Sleegers Kristel 26   VIAFID ORCID Logo  ; Van Broeckhoven Christine 26 ; ten, Kate Mara 27 ; Barkhof Frederik 28 ; Zetterberg Henrik 29   VIAFID ORCID Logo  ; Lovestone Simon 30 ; Streffer Johannes 31 ; Wittig, Michael 32 ; Franke, Andre 32   VIAFID ORCID Logo  ; Tanzi, Rudolph E 2   VIAFID ORCID Logo  ; Visser, Pieter Jelle 5   VIAFID ORCID Logo  ; Bertram, Lars 33   VIAFID ORCID Logo 

1  University of Lübeck, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, Lübeck, Germany (GRID:grid.4562.5) (ISNI:0000 0001 0057 2672) 
2  Massachusetts General Hospital, Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
3  Maastricht University, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht, The Netherlands (GRID:grid.5012.6) (ISNI:0000 0001 0481 6099); Vrije Universiteit Amsterdam, Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
4  Maastricht University, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht, The Netherlands (GRID:grid.5012.6) (ISNI:0000 0001 0481 6099) 
5  Vrije Universiteit Amsterdam, Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
6  University of Gothenburg, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582); Sahlgrenska University Hospital, Clinical Neurochemistry Laboratory, Mölndal, Sweden (GRID:grid.1649.a) (ISNI:000000009445082X) 
7  KU Leuven, Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884); University Hospital Leuven, Neurology Service, Leuven, Belgium (GRID:grid.410569.f) (ISNI:0000 0004 0626 3338) 
8  KU Leuven, Laboratory for Complex Genetics, Department of Human Genetics, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
9  KU Leuven, Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
10  Amsterdam University Medical Centers, Vrije Universiteit, Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
11  University of Antwerp, Department of Biomedical Sciences, Institute Born-Bunge, Antwerp, Belgium (GRID:grid.5284.b) (ISNI:0000 0001 0790 3681) 
12  University of Antwerp, Department of Biomedical Sciences, Institute Born-Bunge, Antwerp, Belgium (GRID:grid.5284.b) (ISNI:0000 0001 0790 3681); UZ Brussel and Vrije Universiteit Brussel (VUB), Department of Neurology and Center for Neurosciences, Brussels, Belgium (GRID:grid.8767.e) (ISNI:0000 0001 2290 8069) 
13  University of Geneva, Geneva, Switzerland (GRID:grid.8591.5) (ISNI:0000 0001 2322 4988); IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy (GRID:grid.419422.8) 
14  AIX Marseille University, INS, Ap-hm, Marseille, France (GRID:grid.462494.9) (ISNI:0000 0004 0541 5643) 
15  GlaxoSmithKline R&D, Neurosciences Therapeutic Area, Stevenage, UK (GRID:grid.462494.9) 
16  University of Lille, Inserm, CHU Lille, Lille, France (GRID:grid.462494.9) 
17  Hospital Clinic I Universitari, Alzheimer’s disease and other cognitive disorders unit, Barcelona, Spain (GRID:grid.410458.c) (ISNI:0000 0000 9635 9413) 
18  University of Gothenburg, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582); University of Oxford, Department of Neuropathology, Nuffield Department of Clinical Neurosciences, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
19  University of Gothenburg, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582) 
20  Barcelona and Centro de Investigación Biomédica en Red en enfermedades Neurodegenerativas (CIBERNED), Memory Unit, Neurology Department, Hospital de Sant Pau, Madrid, Spain (GRID:grid.418264.d) (ISNI:0000 0004 1762 4012) 
21  Geneva University Hospitals, Geriatric Psychiatry, Department of Mental Health and Psychiatry, Geneva, Switzerland (GRID:grid.150338.c) (ISNI:0000 0001 0721 9812); University Hospital of Lausanne, Department of Psychiatry, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662) 
22  University Hospital of Lausanne, Department of Psychiatry, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662) 
23  CITA-Alzheimer Foundation, Department of Neurology, Center for Research and Advanced Therapies, San Sebastian, Spain (GRID:grid.8515.9) 
24  King’s College London, Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); Psychology and Neuroscience (IoPPN), King’s College London, NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); University College London, Health Data Research UK London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University College London, Institute of Health Informatics, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University College London, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
25  Steno Diabetes Center, Copenhagen, Denmark (GRID:grid.419658.7) (ISNI:0000 0004 0646 7285); King’s College London, Institute of Pharmaceutical Sciences, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
26  Center for Molecular Neurology, VIB, Neurodegenerative Brain Diseases Group, Antwerp, Belgium (GRID:grid.11486.3a) (ISNI:0000000104788040); University of Antwerp, Department of Biomedical Sciences, Antwerp, Belgium (GRID:grid.5284.b) (ISNI:0000 0001 0790 3681) 
27  Amsterdam University Medical Centers, Amsterdam Neuroscience, Alzheimer Center and Department of Neurology, Amsterdam, The Netherlands (GRID:grid.484519.5); Amsterdam University Medical Centers, Amsterdam Neuroscience, Department of Radiology and Nuclear Medicine, Amsterdam, The Netherlands (GRID:grid.484519.5) 
28  University College London, Institutes of Neurology and Healthcare Engineering, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
29  University of Gothenburg, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582); Sahlgrenska University Hospital, Clinical Neurochemistry Laboratory, Mölndal, Sweden (GRID:grid.1649.a) (ISNI:000000009445082X); UCL Queen Square Institute of Neurology, Queen Square, Department of Neurodegenerative Disease, London, UK (GRID:grid.436283.8) (ISNI:0000 0004 0612 2631); UK Dementia Research Institute at UCL, London, UK (GRID:grid.436283.8) 
30  University of Oxford, Department of Psychiatry, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
31  University of Antwerp, Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, Antwerp, Belgium (GRID:grid.5284.b) (ISNI:0000 0001 0790 3681); UCB Biopharma SPRL, Translational Medicine Neuroscience, Braine l’Alleud, Belgium (GRID:grid.421932.f) (ISNI:0000 0004 0605 7243) 
32  Christian-Albrechts-University of Kiel, Institute of Clinical Molecular Biology, Kiel, Germany (GRID:grid.9764.c) (ISNI:0000 0001 2153 9986) 
33  University of Lübeck, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Cardiogenetics, Lübeck, Germany (GRID:grid.4562.5) (ISNI:0000 0001 0057 2672); University of Oslo, Department of Psychology, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
21583188
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41398-020-01074-z
ProQuest document ID
2473249780
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.