Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study

被引：2

作者：

Smith, Rebecca G. ^{[1
]}

Pishva, Ehsan ^{[1
,2
]}

Kouhsar, Morteza ^{[1
]}

Imm, Jennifer ^{[1
]}

Dobricic, Valerija ^{[3
]}

Johannsen, Peter ^{[4
]}

Wittig, Michael ^{[5
]}

Franke, Andre ^{[5
]}

Vandenberghe, Rik ^{[6
]}

Schaeverbeke, Jolien ^{[6
]}

Freund-Levi, Yvonne ^{[7
,8
,9
]}

Froelich, Lutz ^{[10
]}

Scheltens, Philip ^{[11
]}

Teunissen, Charlotte E. ^{[12
]}

Frisoni, Giovanni ^{[13
,14
]}

Blin, Olivier ^{[15
]}

Richardson, Jill C. ^{[16
]}

Bordet, Regis ^{[17
]}

Engelborghs, Sebastiaan ^{[18
,19
]}

de Roeck, Ellen ^{[18
]}

Martinez-Lage, Pablo ^{[20
]}

Altuna, Miren ^{[20
]}

Tainta, Mikel ^{[20
]}

Lleo, Alberto ^{[21
]}

Sala, Isabel ^{[21
]}

Popp, Julius ^{[22
]}

Peyratout, Gwendoline ^{[23
]}

Winchester, Laura ^{[24
]}

Nevado-Holgado, Alejo ^{[24
]}

Verhey, Frans ^{[2
]}

Tsolaki, Magda ^{[25
,26
]}

Andreasson, Ulf ^{[27
]}

Blennow, Kaj ^{[27
,28
,29
,30
,31
]}

Zetterberg, Henrik ^{[27
,32
,33
,34
,35
]}

Streffer, Johannes ^{[36
]}

Vos, Stephanie J. B. ^{[2
]}

Lovestone, Simon ^{[23
,37
]}

Visser, Pieter Jelle ^{[2
,11
]}

Bertram, Lars ^{[3
]}

Lunnon, Katie ^{[1
]}

机构：

[1] Univ Exeter, Fac Hlth & Life Sci, Dept Clin & Biomed Sci, Exeter, Devon, England

[2] Maastricht Univ, Fac Hlth Med & Life Sci FHML, Sch Mental Hlth & Neurosci MHeNs, Dept Psychiat & Neuropsychol, Maastricht, Netherlands

[3] Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt LI, Lubeck, Germany

[4] Rigshosp, Danish Dementia Res Ctr, Copenhagen, Denmark

[5] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[6] Katholieke Univ Leuven, Leuven Brain Inst, Lab Cognit Neurol, Leuven, Belgium

[7] Soder Sjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden

[8] Orebro Univ, Sch Med Sci, Orebro, Sweden

[9] Sodertalje Hosp, Dept Geriatr, Sodertalje, Sweden

[10] Heidelberg Univ, Med Fac Mannheim, Dept Geriatr Psychiat, Cent Inst Mental Hlth, Mannheim, Germany

[11] Vrije Univ Amsterdam, Amsterdam Neurosci, Amsterdam UMC, Alzheimer Ctr Amsterdam,Dept Neurol, Amsterdam, Netherlands

[12] Vrije Univ Amsterdam, Amsterdam Neurosci, Amsterdam UMC, Neurochem Lab,Dept Lab Med, Amsterdam, Netherlands

[13] Univ Geneva, Memory Ctr, Geneva, Switzerland

[14] Univ Hosp AMYPAD consortium, Geneva, Switzerland

[15] Aix Marseille Univ, CNRS, Marseille, France

[16] GlaxoSmithKline R&D, Neurosci Therapeut Area, Stevenage, Herts, England

[17] Univ Lille, Lille, France

[18] Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium

[19] Vrije Univ Brussel VUB, Ctr Neurosci C4N, Neuroprotect & Neuromodulat NEUR Res Grp, Jette, Brussels, Belgium

[20] Fdn CITA, Ctr Res & Adv Therapies, Alzheimer Fdn, San Sebastian, Gipuzkoa, Spain

[21] Hosp Santa Creu & Sant Pau, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Serv Neurol, Barcelona, Spain

[22] Univ Zurich, Univ Hosp Psychiat Zurich, Zurich, Switzerland

[23] Univ Hosp Lausanne CHUV, Dept Psychiat, Lausanne, Switzerland

[24] Univ Oxford, Dept Psychiat, Oxford, England

[25] Aristotle Univ Thessaloniki, Ctr Interdisciplinary Res & Innovat, Lab Neurodegenerat Dis, Dept Neurol 1,Sch Med, Thessaloniki, Greece

[26] Alzheimer Hellas, Thessaloniki, Greece

[27] Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Gothenburg, Sweden

[28] Sorbonne Univ, Pitie Salpetriere Hosp, Paris Brain Inst, ICM, Paris, France

[29] Univ Sci & Technol China, Div Life Sci & Med, Inst Aging & Brain Disorders, Neurodegenerat Disorder Res Ctr, Hefei, Peoples R China

[30] Univ Sci & Technol China, Inst Aging & Brain Disorders, Dept Neurol, Hefei, Peoples R China

[31] First Affiliated Hosp USTC, Hefei, Peoples R China

[32] UCL, Dept Neurodegenerat Dis, Inst Neurol, Queen Sq, London, England

[33] UCL, UK Dementia Res Inst, London, England

[34] Hong Kong Ctr Neurodegenerat Dis, Shatin, Hong Kong, Peoples R China

[35] Univ Wisconsin, Wisconsin Alzheimers Dis Res Ctr, Sch Med & Publ Hlth, Madison, WI USA

[36] UCB Biopharm SRL, Translat Med Neurosci, Brussels, Belgium

[37] Johnson & Johnson Innovat Med, Beerse, Belgium

来源：

ALZHEIMERS & DEMENTIA | 2024年 / 20卷 / 10期

基金：

瑞士国家科学基金会; 英国医学研究理事会; 新加坡国家研究基金会; 瑞典研究理事会;

关键词：

Alzheimer's disease (AD); amyloid; biomarker; blood; cerebrospinal fluid (CSF); DNA methylation; 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; YKL-40; TAU; METHYLATION; BRAIN; DIAGNOSIS; PACKAGE; BETA; NEUROPATHOLOGY; IDENTIFICATION; METAANALYSIS; NEUROGRANIN;

D O I：

10.1002/alz.14098

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：6722 / 6739

页数：18

共 73 条

[1] Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays [J].

Aryee, Martin J. ;

Jaffe, Andrew E. ;

Corrada-Bravo, Hector ;

Ladd-Acosta, Christine ;

Feinberg, Andrew P. ;

Hansen, Kasper D. ;

Irizarry, Rafael A. .

BIOINFORMATICS, 2014, 30 (10) :1363-1369

[2]

Blurton-Jones Mathew, 2006, Current Alzheimer Research, V3, P437, DOI 10.2174/156720506779025242

[3] The EMIF-AD Multimodal Biomarker Discovery study: design, methods and cohort characteristics [J].

Bos, Isabelle ;

Vos, Stephanie ;

Vandenberghe, Rik ;

Scheltens, Philip ;

Engelborghs, Sebastiaan ;

Frisoni, Giovanni ;

Luis Molinuevo, Jose ;

Wallin, Anders ;

Lleo, Alberto ;

Popp, Julius ;

Martinez-Lage, Pablo ;

Baird, Alison ;

Dobson, Richard ;

Legido-Quigley, Cristina ;

Sleegers, Kristel ;

Van Broeckhoven, Christine ;

Bertram, Lars ;

ten Kate, Mara ;

Barkhof, Frederik ;

Zetterberg, Henrik ;

Lovestone, Simon ;

Streffer, Johannes ;

Visser, Pieter Jelle .

ALZHEIMERS RESEARCH & THERAPY, 2018, 10

[4] NEUROPATHOLOGICAL STAGING OF ALZHEIMER-RELATED CHANGES [J].

BRAAK, H ;

BRAAK, E .

ACTA NEUROPATHOLOGICA, 1991, 82 (04) :239-259

[5] Demonstration of Amyloid Deposits and Neurofibrillary Changes in Whole Brain Sections [J].

Braak, Heiko ;

Braak, Eva .

BRAIN PATHOLOGY, 1991, 1 (03) :213-216

[6] CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease [J].

Buerger, Katharina ;

Ewers, Michael ;

Pirttila, Tuula ;

Zinkowski, Raymond ;

Alafuzoff, Irina ;

Teipel, Stefan J. ;

DeBernardis, John ;

Kerkman, Daniel ;

McCulloch, Cheryl ;

Soininen, Hilkka ;

Hampel, Harald .

BRAIN, 2006, 129 :3035-3041

[7] Plasma level of chitinase 3-like 1 protein increases in patients with early Alzheimer's disease [J].

Choi, Jihye ;

Lee, Ho-Won ;

Suk, Kyoungho .

JOURNAL OF NEUROLOGY, 2011, 258 (12) :2181-2185

[8] Biomarkers for the Early Detection and Progression of Alzheimer's Disease [J].

Counts, Scott E. ;

Ikonomovic, Milos D. ;

Mercado, Natosha ;

Vega, Irving E. ;

Mufson, Elliott J. .

NEUROTHERAPEUTICS, 2017, 14 (01) :35-53

[9] Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People [J].

De Meyer, Geert ;

Shapiro, Fred ;

Vanderstichele, Hugo ;

Vanmechelen, Eugeen ;

Engelborghs, Sebastiaan ;

De Deyn, Peter Paul ;

Coart, Els ;

Hansson, Oskar ;

Minthon, Lennart ;

Zetterberg, Henrik ;

Blennow, Kaj ;

Shaw, Leslie ;

Trojanowski, John Q. .

ARCHIVES OF NEUROLOGY, 2010, 67 (08) :949-956

[10] CSF tau markers are correlated with hippocampal volume in Alzheimer's disease [J].

de Souza, Leonardo C. ;

Chupin, Marie ;

Lamari, Foudil ;

Jardel, Claude ;

Leclercq, Delphine ;

Colliot, Olivier ;

Lehericy, Stephane ;

Dubois, Bruno ;

Sarazin, Marie .

NEUROBIOLOGY OF AGING, 2012, 33 (07) :1253-1257

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