Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD studyLübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
Danish Dementia Research Centre, Rigshospitalet, Copenhagen, Denmark.
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Laboratory for Cognitive Neurology, KU Leuven, Leuven Brain Institute, Leuven, Belgium.
Laboratory for Cognitive Neurology, KU Leuven, Leuven Brain Institute, Leuven, Belgium.
Department of Geriatric Psychiatry, Central Institut of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
Neurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
Memory center, Geneva University and University Hospitals; AMYPAD consortium, Geneva, Switzerland.
Aix-Marseille University-CNRS, Marseille, France.
Neuroscience Therapeutic Area, GlaxoSmithKline R&D, Stevenage, Hertfordshire, UK.
Université de Lille, Lille, Cedex, France.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neuroprotection & Neuromodulation (NEUR) Research Group, Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Jette, Brussels, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Center for Research and Advanced Therapies, Fundación CITA-Alzhéimer Fundazioa, San Sebastian, Gipuzkoa, Spain.
Center for Research and Advanced Therapies, Fundación CITA-Alzhéimer Fundazioa, San Sebastian, Gipuzkoa, Spain.
Center for Research and Advanced Therapies, Fundación CITA-Alzhéimer Fundazioa, San Sebastian, Gipuzkoa, Spain.
Servicio de Neurología, Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Hospital Sant Pau, Barcelona, Spain.
Servicio de Neurología, Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Hospital Sant Pau, Barcelona, Spain.
University Hospital of Psychiatry Zürich, University of Zürich, Zürich, Switzerland.
Department of Psychiatry, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
Department of Psychiatry, University of Oxford, Oxford, UK.
Department of Psychiatry, University of Oxford, Oxford, UK.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, The Netherlands.
1st Department of Neurology, School of Medicine, Laboratory of Neurodegenerative Diseases, Center for Interdisciplinary Research and Innovation, Aristotle University of Thessaloniki, and Alzheimer Hellas, Thessaloniki, Greece.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden; Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, PR China.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Center for Neurodegenerative Diseases, N.T., Shatin, Hong Kong, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Translational Medicine Neuroscience, UCB Biopharma SRL, Brussels, Belgium.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, The Netherlands.
Department of Psychiatry, University Hospital of Lausanne (CHUV), Lausanne, Switzerland; Johnson & Johnson Innovative Medicines, Beerse, Belgium.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, The Netherlands; Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, Devon, UK.
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2024 (English)In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 20, no 10, p. 6722-6739Article in journal (Refereed) Published
Abstract [en]
INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration.
METHODS: 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.
DISCUSSION: 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.
HIGHLIGHTS: 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.
Place, publisher, year, edition, pages
John Wiley & Sons, 2024. Vol. 20, no 10, p. 6722-6739
Keywords [en]
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
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:oru:diva-115683DOI: 10.1002/alz.14098ISI: 001300071700001PubMedID: 39193893Scopus ID: 2-s2.0-85202547146OAI: oai:DiVA.org:oru-115683DiVA, id: diva2:1893221
Funder
EU, FP7, Seventh Framework Programme, FP7/2007- 2013Swedish Research Council, #2022-01018; #2017-00915; #2019-02397EU, Horizon Europe, 101053962Stiftelsen Gamla TjänarinnorThe Swedish Brain Foundation, #FO2022-0270EU, Horizon 2020, 860197Alzheimerfonden, #AF-930351; #AF-939721; #AF-968270Region Örebro County, AFA 200386
Note
Funding information: Innovative Medicines Initiative Joint Undertaking, Grant/Award Number: 115372; European Union’s Seventh Framework Program, Grant/Award Number: FP7/2007-2013; Alzheimer’s Society, Grant/Award Number: AS-PG-14-038; Medical Research Council (MRC), Grant/Award Number: MR/S011625/1; National Institute on Aging, Grant/Award Number: R01AG067015; ZonMw Memorabel/Alzheimer Nederland, Grant/Award Number: 733050516; Stichting Alzheimer Onderzoek, Grant/Award Numbers: #13007, #11020, #2017-032; Flemish Government, Grant/Award Number: VIND IWT 135043; Fonds Wetenschappelijk Onderzoek, Grant/Award Number: #12Y1620N; Department of Health of the Basque Government, Grant/Award Numbers: 2016111096, S-PR12CH001, S-PR13ZH001; Carlos III Institute Ministry of Health Government of Spain, Grant/Award Number: PI12/02262; Swiss National Science Foundation, Grant/Award Numbers: #320030_141179, 320030_204886; Synapsis Foundation—Dementia Research Switzerland, Grant/Award Number: #2017-PI01; Swedish Research Council, Grant/Award Numbers: #2022-01018, #2017-00915, #2019-02397; European Union’s Horizon Europe research and innovation programme, Grant/Award Number: 101053962; Swedish State Support for Clinical Research, Grant/Award Number: #ALFGBG-71320; Alzheimer Drug Discovery Foundation, Grant/Award Number: #201809-2016862; AD Strategic Fund and the Alzheimer’s Association, Grant/Award Numbers: #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C; Bluefield Project; Olav Thon Foundation; Erling-Persson Family Foundation; Stiftelsen för Gamla Tjänarinnor; Hjärnfonden, Grant/Award Number: #FO2022-0270; European Union’s Horizon 2020 research and innovation programme, Grant/Award Number: 860197; European Union Joint Programme—Neurodegenerative Disease Research, Grant/Award Number: JPND2021-00694; National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre; UK Dementia Research Institute, Grant/Award Number: UKDRI-1003; Swiss National Research Foundation, Grant/Award Number: SNF 320030_141179; Swedish Alzheimer Foundation, Grant/Award Numbers: #AF-930351, #AF-939721, #AF-968270; Swedish government and the County Councils; ALF-agreement, Grant/Award Numbers: #ALFGBG-715986, #ALFGBG-965240; European Union Joint Program for Neurodegenerative Disorders, Grant/Award Number: JPND2019-466-236; Alzheimer’s Association 2021 Zenith Award, Grant/Award Number: ZEN-21-848495; Alzheimer’s Association, Grant/Award Number: SG-23-1038904 QC; The Brain Foundation, Grant/Award Number: FO2018-0315; Stohne’s Foundation; Gamla Tjänarinnor Stftelse; Stohnes Stiftelse, Särfond 31S Research Fund Region Örebro län Sweden, Grant/Award Number: AFA 200386.
2024-08-292024-08-292024-11-06Bibliographically approved