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

Rebecca G. Smith; Ehsan Pishva; Morteza Kouhsar; Jennifer Imm; Valerija Dobricic; Peter Johannsen; Michael Wittig; Andre Franke; Rik Vandenberghe; Jolien Schaeverbeke; Yvonne Freund-Levi; Lutz Frölich; Philip Scheltens; Charlotte E. Teunissen; Giovanni Frisoni; Olivier Blin; Jill C. Richardson; Régis Bordet; Sebastiaan Engelborghs; Ellen de Roeck; Pablo Martinez-Lage; Miren Altuna; Mikel Tainta; Alberto Lleó; Isabel Sala; Julius Popp; Gwendoline Peyratout; Laura Winchester; Alejo Nevado-Holgado; Frans Verhey; Magda Tsolaki; Ulf Andreasson; Kaj Blennow; Henrik Zetterberg; Johannes Streffer; Stephanie J.B. Vos; Simon Lovestone; Pieter Jelle Visser; Lars Bertram; Katie Lunnon

doi:10.1002/alz.14098

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

Rebecca G. Smith, Ehsan Pishva, Morteza Kouhsar, Jennifer Imm, Valerija Dobricic, Peter Johannsen, Michael Wittig, Andre Franke, Rik Vandenberghe, Jolien Schaeverbeke, Yvonne Freund-Levi, Lutz Frölich, Philip Scheltens, Charlotte E. Teunissen, Giovanni Frisoni, Olivier Blin, Jill C. Richardson, Régis Bordet, Sebastiaan Engelborghs, Ellen de RoeckPablo Martinez-Lage, Miren Altuna, Mikel Tainta, Alberto Lleó, Isabel Sala, Julius Popp, Gwendoline Peyratout, Laura Winchester, Alejo Nevado-Holgado, Frans Verhey, Magda Tsolaki, Ulf Andreasson, Kaj Blennow, Henrik Zetterberg, Johannes Streffer, Stephanie J.B. Vos, Simon Lovestone, Pieter Jelle Visser, Lars Bertram, Katie Lunnon^*

^*Corresponding author for this work

9 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Alzheimer's and Dementia
Volume	20
Issue number	10
Pages (from-to)	6722-6739
Number of pages	18
ISSN	1552-5260
DOIs	https://doi.org/10.1002/alz.14098
Publication status	Published - 10.2024

Research Areas and Centers

Research Area: Medical Genetics

DFG Research Classification Scheme

2.23-06 Molecular and Cellular Neurology and Neuropathology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/alz.14098

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Smith, R. G., Pishva, E., Kouhsar, M., Imm, J., Dobricic, V., Johannsen, P., Wittig, M., Franke, A., Vandenberghe, R., Schaeverbeke, J., Freund-Levi, Y., Frölich, L., Scheltens, P., Teunissen, C. E., Frisoni, G., Blin, O., Richardson, J. C., Bordet, R., Engelborghs, S., ... Lunnon, K. (2024). Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study. Alzheimer's and Dementia, 20(10), 6722-6739. https://doi.org/10.1002/alz.14098

@article{3ae446ff1f5c4c1f9c83537322c8322a,

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

abstract = "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.",

author = "Smith, \{Rebecca G.\} and Ehsan Pishva and Morteza Kouhsar and Jennifer Imm and Valerija Dobricic and Peter Johannsen and Michael Wittig and Andre Franke and Rik Vandenberghe and Jolien Schaeverbeke and Yvonne Freund-Levi and Lutz Fr{\"o}lich and Philip Scheltens and Teunissen, \{Charlotte E.\} and Giovanni Frisoni and Olivier Blin and Richardson, \{Jill C.\} and R{\'e}gis Bordet and Sebastiaan Engelborghs and \{de Roeck\}, Ellen and Pablo Martinez-Lage and Miren Altuna and Mikel Tainta and Alberto Lle{\'o} and Isabel Sala and Julius Popp and Gwendoline Peyratout and Laura Winchester and Alejo Nevado-Holgado and Frans Verhey and Magda Tsolaki and Ulf Andreasson and Kaj Blennow and Henrik Zetterberg and Johannes Streffer and Vos, \{Stephanie J.B.\} and Simon Lovestone and Visser, \{Pieter Jelle\} and Lars Bertram and Katie Lunnon",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = oct,

doi = "10.1002/alz.14098",

language = "English",

volume = "20",

pages = "6722--6739",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc",

number = "10",

}

Smith, RG, Pishva, E, Kouhsar, M, Imm, J, Dobricic, V, Johannsen, P, Wittig, M, Franke, A, Vandenberghe, R, Schaeverbeke, J, Freund-Levi, Y, Frölich, L, Scheltens, P, Teunissen, CE, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Engelborghs, S, de Roeck, E, Martinez-Lage, P, Altuna, M, Tainta, M, Lleó, A, Sala, I, Popp, J, Peyratout, G, Winchester, L, Nevado-Holgado, A, Verhey, F, Tsolaki, M, Andreasson, U, Blennow, K, Zetterberg, H, Streffer, J, Vos, SJB, Lovestone, S, Visser, PJ, Bertram, L & Lunnon, K 2024, 'Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study', Alzheimer's and Dementia, vol. 20, no. 10, pp. 6722-6739. https://doi.org/10.1002/alz.14098

TY - JOUR

T1 - Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study

AU - Smith, Rebecca G.

AU - Pishva, Ehsan

AU - Kouhsar, Morteza

AU - Imm, Jennifer

AU - Dobricic, Valerija

AU - Johannsen, Peter

AU - Wittig, Michael

AU - Franke, Andre

AU - Vandenberghe, Rik

AU - Schaeverbeke, Jolien

AU - Freund-Levi, Yvonne

AU - Frölich, Lutz

AU - Scheltens, Philip

AU - Teunissen, Charlotte E.

AU - Frisoni, Giovanni

AU - Blin, Olivier

AU - Richardson, Jill C.

AU - Bordet, Régis

AU - Engelborghs, Sebastiaan

AU - de Roeck, Ellen

AU - Martinez-Lage, Pablo

AU - Altuna, Miren

AU - Tainta, Mikel

AU - Lleó, Alberto

AU - Sala, Isabel

AU - Popp, Julius

AU - Peyratout, Gwendoline

AU - Winchester, Laura

AU - Nevado-Holgado, Alejo

AU - Verhey, Frans

AU - Tsolaki, Magda

AU - Andreasson, Ulf

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Streffer, Johannes

AU - Vos, Stephanie J.B.

AU - Lovestone, Simon

AU - Visser, Pieter Jelle

AU - Bertram, Lars

AU - Lunnon, Katie

PY - 2024/10

Y1 - 2024/10

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85202547146

U2 - 10.1002/alz.14098

DO - 10.1002/alz.14098

M3 - Journal articles

C2 - 39193893

AN - SCOPUS:85202547146

SN - 1552-5260

VL - 20

SP - 6722

EP - 6739

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 10

ER -

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

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