Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study
Smith, R.G. (University of Exeter)
Pishva, E. (Maastricht University)
Kouhsar, M. (University of Exeter)
Imm, J. (University of Exeter)
Dobricic, V. (University of Lübeck)
Johannsen, Peter (Danish Dementia Research Centre)
Wittig, M. (Christian-Albrechts-University of Kiel)
Franke, A. (Christian-Albrechts-University of Kiel)
Vandenberghe, R. (Leuven Brain Institute)
Schaeverbeke, J. (Leuven Brain Institute)
Freund-Levi, Y. (Södertälje Hospital)
Frölich, L. (Medical Faculty Mannheim/Heidelberg University)
Scheltens, P. (Amsterdam University Medical Center (UMC))
Teunissen, C.E. (Vrije Universiteit Amsterdam)
Frisoni, G. (Geneva University and University Hospitals)
Blin, O. (Aix-Marseille University-CNRS)
Richardson, J.C. (GlaxoSmithKline R&D (Regne Unit))
Bordet, R. (Université de Lille)
Engelborghs, S. (Vrije Universiteit Brussel (VUB))
de Roeck, E. (University of Antwerp)
Martinez-Lage, P. (Fundación CITA Alzheimer (Sant Sebastià, País Basc))
Altuna-Azkargorta, Miren (Fundación CITA Alzheimer (Sant Sebastià, País Basc))
Tainta, M. (Fundación CITA Alzheimer (Sant Sebastià, País Basc))
Lleó, Alberto (Institut de Recerca Sant Pau)
Sala, Isabel (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Popp, J. (University of Zürich)
Peyratout, G. (University Hospital of Lausanne (CHUV))
Winchester, L. (University of Oxford)
Nevado-Holgado, Alejo (University of Oxford)
Verhey, F. (Maastricht University)
Tsolaki, M. (1st Aristotle University of Thessaloniki)
Andreasson, Ulf (The Sahlgrenska Academy at University of Gothenburg)
Blennow, K. (University of Science and Technology of China and First Affiliated Hospital of USTC)
Zetterberg, H. (University of Wisconsin-Madison)
Streffer, J. (UCB Biopharma SRL)
Vos, S.J.B. (Maastricht University)
Lovestone, S. (Johnson & Johnson Innovative Medicines)
Visser, P.J. (Amsterdam University Medical Center (UMC))
Bertram, L. (University of Lübeck)
Lunnon, K. (University of Exeter)
Universitat Autònoma de Barcelona

Date:	2024
Abstract:	We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development. We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain. Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.
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 (AD) ; DNA methylation ; YKL-40 ; Amyloid ; Biomarker ; Blood ; Cerebrospinal fluid (CSF) ; Epigenetics ; Epigenome-wide association study (EWAS) ; Genome-wide association study (GWAS) ; Methylation quantitative trait loci (mQTL) ; Mild cognitive impairment (MCI) ; Neurofilament light (NfL) ; Protein quantitative trait loci (pQTL) ; Tau
Published in:	Alzheimer's & dementia, Vol. 20 Núm. 10 (october 2024) , p. 6722-6739, ISSN 1552-5279

DOI: 10.1002/alz.14098
PMID: 39193893

18 p, 2.3 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
Articles > Published articles