Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning
Neumann, Alexander (University of Antwerp (Bèlgica))
Ohlei, Olena (University of Lübeck (Alemanya))
Küçükali, Fahri (University of Antwerp (Bèlgica))
Bos, Isabelle (Netherlands Institute for Health Services Research (NIVEL))
Timsina, Jigyasha (Washington University School of Medicine (Estats Units d'Amèrica))
Vos, Stephanie J.B. (Maastricht University (Païssos Baixos))
Prokopenko, Dmitry (Massachusetts General Hospital (Boston, Estats Units d'Amèrica))
Tijms, Betty M. (Vrije Universiteit Amsterdam)
Andreasson, Ulf (Sahlgrenska University Hospital (Suècia))
Blennow, Kaj (Sahlgrenska University Hospital (Suècia))
Vandenberghe, Rik (University Hospital Leuven (Bèlgica))
Scheltens, Philip (Vrije Universiteit Amsterdam)
Teunissen, Charlotte E. (Amsterdam University Medical Center (UMC))
Engelborghs, Sebastiaan (Vrije Universiteit Brussel (Païssos Baixos))
Frisoni, Giovanni B. (Geneva University and University Hospitals (Suïssa))
Blin, Oliver (Marseille University Hospital (França))
Richardson, Jill (GlaxoSmithKline R&D (Regne Unit))
Bordet, Régis (University of Lille (França))
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Alcolea, Daniel (Institut d'Investigació Biomèdica Sant Pau)
Popp, Julius (University Hospital of Lausanne (Suïssa))
Marsh, Thomas (Washington University in St. Louis (Estats Units d'Amèrica))
Gorijala, Priyanka (Washington University School of Medicine)
Clark, Christopher (University of Zürich (Suïssa))
Peyratout, Gwendoline (Lausanne University Hospital)
Martinez-Lage, Pablo (Fundación CITA-Alzhéimer Fundazioa (San Sebastián, País Basc))
Tainta, Mikel (Hospital de Zumárraga (Guipúscoa, País Basc)))
Dobson, Richard James Butler (University College London (Regne Unit))
Legido-Quigley, Cristina (King's College London)
Van Broeckhoven, Christine (VIB Center for Molecular Neurology (Bèlgica, Païssos Baixos))
Tanzi, Rudolph E. (Massachusetts General Hospital (Boston))
ten Kate, Mara (Amsterdam University Medical Center (UMC))
Lill, Christina (University of Münster (Alemanya))
Barkhof, Frederik (University College London (Regne Unit))
Cruchaga, Carlos (Washington University School of Medicine (Estats Units d'Amèrica))
Lovestone, Simon (University of Oxford)
Streffer, Johannes Rolf (Janssen R&D (Bèlgica, Païssos Baixos))
Zetterberg, Henrik (Hong Kong Center for Neurodegenerative Diseases)
Visser, Pieter Jelle (Maastricht University (Països Baixos))
Sleegers, Kristel (University of Antwerp (Bèlgica))
Bertram, Lars (University of Oslo)
Universitat Autònoma de Barcelona

Date:	2023
Abstract:	Genome-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. We 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. Five 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. These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Alzheimer's disease ; Biomarkers ; Cerebrospinal fluid (CSF) ; Dementia ; Genome-wide association study (GWAS) ; Mediation ; Multivariate analysis ; Principal component analysis ; Structural equation modeling
Published in:	Genome medicine, Vol. 15 Núm. 1 (december 2023) , p. 79, ISSN 1756-994X

DOI: 10.1186/s13073-023-01233-z
PMID: 37794492

23 p, 7.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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