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

[21] Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B [J].

Klunk, WE ;

Engler, H ;

Nordberg, A ;

Wang, YM ;

Blomqvist, G ;

Holt, DP ;

Bergström, M ;

Savitcheva, I ;

Huang, GF ;

Estrada, S ;

Ausén, B ;

Debnath, ML ;

Barletta, J ;

Price, JC ;

Sandell, J ;

Lopresti, BJ ;

Wall, A ;

Koivisto, P ;

Antoni, G ;

Mathis, CA ;

Långström, B .

ANNALS OF NEUROLOGY, 2004, 55 (03) :306-319

[22]

Koetsier J., 2023, medRxiv, DOI [10.1002/alz.14061, DOI 10.1002/ALZ.14061]

[23] Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing [J].

Kunkle, Brian W. ;

Grenier-Boley, Benjamin ;

Sims, Rebecca ;

Bis, Joshua C. ;

Damotte, Vincent ;

Naj, Adam C. ;

Boland, Anne ;

Vronskaya, Maria ;

van der Lee, Sven J. ;

Amlie-Wolf, Alexandre ;

Bellenguez, Celine ;

Frizatti, Aura ;

Chouraki, Vincent ;

Martin, Eden R. ;

Sleegers, Kristel ;

Badarinarayan, Nandini ;

Jakobsdottir, Johanna ;

Hamilton-Nelson, Kara L. ;

Moreno-Grau, Sonia ;

Olaso, Robert ;

Raybould, Rachel ;

Chen, Yuning ;

Kuzma, Amanda B. ;

Hiltunen, Mikko ;

Morgan, Taniesha ;

Ahmad, Shahzad ;

Vardarajan, Badri N. ;

Epelbaum, Jacques ;

Hoffmann, Per ;

Boada, Merce ;

Beecham, Gary W. ;

Garnier, Jean-Guillaume ;

Harold, Denise ;

Fitzpatrick, Annette L. ;

Valladares, Otto ;

Moutet, Marie-Laure ;

Gerrish, Amy ;

Smith, Albert, V ;

Qu, Liming ;

Bacq, Delphine ;

Denning, Nicola ;

Jian, Xueqiu ;

Zhao, Yi ;

Del Zompo, Maria ;

Fox, Nick C. ;

Choi, Seung-Hoan ;

Mateo, Ignacio ;

Hughes, Joseph T. ;

Adams, Hieab H. ;

Malamon, John .

NATURE GENETICS, 2019, 51 (03) :414-+

[24] WGCNA: an R package for weighted correlation network analysis [J].

Langfelder, Peter ;

Horvath, Steve .

BMC BIOINFORMATICS, 2008, 9 (1)

[25] The sva package for removing batch effects and other unwanted variation in high-throughput experiments [J].

Leek, Jeffrey T. ;

Johnson, W. Evan ;

Parker, Hilary S. ;

Jaffe, Andrew E. ;

Storey, John D. .

BIOINFORMATICS, 2012, 28 (06) :882-883

[26] Neurochemical diagnosis of Alzheimer's dementia by CSF Aβ42, Aβ42/Aβ40 ratio and total tau [J].

Lewczuk, P ;

Esselmann, H ;

Otto, M ;

Maler, JM ;

Henkel, AW ;

Henkel, MK ;

Eikenberg, O ;

Antz, C ;

Krause, WR ;

Reulbach, U ;

Kornhuber, J ;

Wiltfang, J .

NEUROBIOLOGY OF AGING, 2004, 25 (03) :273-281

[27] Biomarkers of Alzheimer's disease and mild cognitive impairment: A current perspective [J].

Lewczuk, Piotr ;

Mroczko, Barbara ;

Fagan, Anne ;

Kornhuber, Johannes .

ADVANCES IN MEDICAL SCIENCES, 2015, 60 (01) :76-82

[28] Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease [J].

Lunnon, Katie ;

Smith, Rebecca ;

Hannon, Eilis ;

De Jager, Philip L. ;

Srivastava, Gyan ;

Volta, Manuela ;

Troakes, Claire ;

Al-Sarraj, Safa ;

Burrage, Joe ;

Macdonald, Ruby ;

Condliffe, Daniel ;

Harries, Lorna W. ;

Katsel, Pavel ;

Haroutunian, Vahram ;

Kaminsky, Zachary ;

Joachim, Catharine ;

Powell, John ;

Lovestone, Simon ;

Bennett, David A. ;

Schalkwyk, Leonard C. ;

Mill, Jonathan .

NATURE NEUROSCIENCE, 2014, 17 (09) :1164-1170

[29] Mitochondrial Dysfunction and Immune Activation are Detectable in Early Alzheimer's Disease Blood [J].

Lunnon, Katie ;

Ibrahim, Zina ;

Proitsi, Petroula ;

Lourdusamy, Anbarasu ;

Newhouse, Stephen ;

Sattlecker, Martina ;

Furney, Simon ;

Saleem, Muzamil ;

Soininen, Hilkka ;

Kloszewska, Iwona ;

Mecocci, Patrizia ;

Tsolaki, Magda ;

Vellas, Bruno ;

Coppola, Giovanni ;

Geschwind, Daniel ;

Simmons, Andrew ;

Lovestone, Simon ;

Dobson, Richard ;

Hodges, Angela .

JOURNAL OF ALZHEIMERS DISEASE, 2012, 30 (03) :685-710

[30] Distinctive patterns of DNA methylation associated with Parkinson disease Identification of concordant epigenetic changes in brain and peripheral blood leukocytes [J].

Masliah, Eliezer ;

Dumaop, Wilmar ;

Galasko, Douglas ;

Desplats, Paula .

EPIGENETICS, 2013, 8 (10) :1030-1038

← 1 2 3 4 5 6 7 8 →