Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Genome Medicine

Research

Betty M. Tijms¹  Philip Scheltens¹  Mara ten Kate²  Stephanie Vos³  Pablo Martinez-Lage⁴  Mikel Tainta⁵  Oliver Blin⁶  Kristel Sleegers⁷  Fahri Küçükali⁷  Alexander Neumann⁸  Johannes Streffer⁹  Pieter Jelle Visser^1,10  Sebastiaan Engelborghs^1,11  Christine Van Broeckhoven^1,12  Richard J. B. Dobson^1,13  Kaj Blennow^1,14  Ulf Andreasson^1,14  Henrik Zetterberg^1,15  Christopher Clark^1,16  Julius Popp^1,17  Gwendoline Peyratout^1,18  Jigyasha Timsina^1,19  Priyanka Gorijala^1,19  Thomas W. Marsh^2,20  Carlos Cruchaga^2,21  Frederik Barkhof^2,22  Rudolph E. Tanzi^2,23  Dmitry Prokopenko^2,23  Simon Lovestone^2,24  Rik Vandenberghe^2,25  Olena Ohlei^2,26  Lars Bertram^2,27  Christina M. Lill^2,28  Giovanni B. Frisoni^2,29  Alberto Lleó^3,30  Daniel Alcolea^3,30  Isabelle J. Bos^3,31  Charlotte E. Teunissen^3,32  Régis Bordet^3,33  Jill C. Richardson^3,34  Cristina Legido-Quigley^3,35 

[1] Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands;Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands;Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands;Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands;Center for Research and Advanced Therapies, CITA—Alzheimer Foundation, San Sebastian, Spain;Center for Research and Advanced Therapies, CITA—Alzheimer Foundation, San Sebastian, Spain;Zumarraga Hospital, Osakidetza, Integrated Health Organization (OSI) Goierri-Urola Garia, Basque Country, Spain;Clinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital, Marseille, France;Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium;Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium;Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, Netherlands;Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;AC Immune SA, Lausanne, Switzerland;Janssen R&D, LLC, Beerse, Belgium;Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands;Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, Netherlands;Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;Department of Neurology and Memory Clinic, Universitair Ziekenhuis Brussel (UZ Brussel) and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium;Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium;Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Boston, 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, London, UK;Health Data Research UK London, University College London, London, UK;Institute of Health Informatics, University College London, London, UK;The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK;Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden;Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden;Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden;Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden;Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK;UK Dementia Research Institute, University College London, London, UK;Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China;Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zurich, Switzerland;Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zurich, Switzerland;Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland;Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland;Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA;NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA;Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA;NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA;Division of Biology & Biomedical Sciences, Washington University in St. Louis, St Louis, MO, USA;Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA;NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA;Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA;Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands;Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK;Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA;Janssen Medical Ltd, Wycombe, UK;Department of Psychiatry, University of Oxford, Oxford, UK;Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium;Neurology Service, University Hospital Leuven, Leuven, Belgium;Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Ratzeburger Allee 160, V50.2M, 23562, Lübeck, Germany;Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Ratzeburger Allee 160, V50.2M, 23562, Lübeck, Germany;Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway;Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Ratzeburger Allee 160, V50.2M, 23562, Lübeck, Germany;Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany;Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London, UK;Memory Center, Department of Rehabilitation and Geriatrics, Geneva University and University Hospitals, Geneva, Switzerland;Memory Unit, Neurology Department, Hospital de Sant Pau, Barcelona, Spain;Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;Netherlands Institute for Health Services Research, Utrecht, Netherlands;Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands;Neuroscience & Cognition, CHU de Lille, University of Lille, Inserm, France;Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK;Steno Diabetes Center, Copenhagen, Denmark;Institute of Pharmaceutical Science, King’s College London, London, UK;

关键词: Alzheimer’s disease;    Dementia;    Biomarkers;    Cerebrospinal fluid (CSF);    Genome-wide association study (GWAS);    Multivariate analysis;    Principal component analysis;    Mediation;    Structural equation modeling;   

DOI  :  10.1186/s13073-023-01233-z

 received in 2023-07-24, accepted in 2023-09-12,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundGenome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.MethodsWe performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.ResultsFive loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.ConclusionsThese results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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