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

R.G. Smith; E. Pishva; M. Kouhsar; J. Imm; V. Dobricic; P. Johannsen; M. Wittig; A. Franke; R. Vandenberghe; J. Schaeverbeke; Y. Freund-Levi; L. Frölich; P. Scheltens; C.E. Teunissen; G. Frisoni; O. Blin; J.C. Richardson; R. Bordet; S. Engelborghs; E. de Roeck; P. Martinez-Lage; M. Altuna; M. Tainta; Alberto Lleó; Isabel Sala; J. Popp; G. Peyratout; L. Winchester; A. Nevado-Holgado; F. Verhey; M. Tsolaki; U. Andreasson; K. Blennow; H. Zetterberg; J. Streffer; S.J.B. Vos; S. Lovestone; P.J. Visser; L. Bertram; K. Lunnon

doi:10.1002/alz.14098

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

R.G. Smith, E. Pishva, M. Kouhsar, J. Imm, V. Dobricic, P. Johannsen, M. Wittig, A. Franke, R. Vandenberghe, J. Schaeverbeke, Y. Freund-Levi, L. Frölich, P. Scheltens, C.E. Teunissen, G. Frisoni, O. Blin, J.C. Richardson, R. Bordet, S. Engelborghs, E. de RoeckP. Martinez-Lage, M. Altuna, M. Tainta, Alberto Lleó, Isabel Sala, J. Popp, G. Peyratout, L. Winchester, A. Nevado-Holgado, F. Verhey, M. Tsolaki, U. Andreasson, K. Blennow, H. Zetterberg, J. Streffer, S.J.B. Vos, S. Lovestone, P.J. Visser, L. Bertram, K. Lunnon

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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.

Idioma original	Anglès
Pàgines (de-a)	6722-6739
Nombre de pàgines	18
Revista	Alzheimer's and Dementia
Volum	20
Número	10
DOIs	https://doi.org/10.1002/alz.14098
Estat de la publicació	Publicada - 2024

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10.1002/alz.14098

https://ddd.uab.cat/record/309043

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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{0de1d6ab3ddf487c9b9fcfad97280313,

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

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.",

keywords = "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",

author = "R.G. Smith and E. Pishva and M. Kouhsar and J. Imm and V. Dobricic and P. Johannsen and M. Wittig and A. Franke and R. Vandenberghe and J. Schaeverbeke and Y. Freund-Levi and L. Fr{\"o}lich and P. Scheltens and C.E. Teunissen and G. Frisoni and O. Blin and J.C. Richardson and R. Bordet and S. Engelborghs and {de Roeck}, E. and P. Martinez-Lage and M. Altuna and M. Tainta and Alberto Lle{\'o} and Isabel Sala and J. Popp and G. Peyratout and L. Winchester and A. Nevado-Holgado and F. Verhey and M. Tsolaki and U. Andreasson and K. Blennow and H. Zetterberg and J. Streffer and S.J.B. Vos and S. Lovestone and P.J. Visser and L. Bertram and K. Lunnon",

year = "2024",

doi = "10.1002/alz.14098",

language = "English",

volume = "20",

pages = "6722--6739",

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, núm. 10, pàg. 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, R.G.

AU - Pishva, E.

AU - Kouhsar, M.

AU - Imm, J.

AU - Dobricic, V.

AU - Johannsen, P.

AU - Wittig, M.

AU - Franke, A.

AU - Vandenberghe, R.

AU - Schaeverbeke, J.

AU - Freund-Levi, Y.

AU - Frölich, L.

AU - Scheltens, P.

AU - Teunissen, C.E.

AU - Frisoni, G.

AU - Blin, O.

AU - Richardson, J.C.

AU - Bordet, R.

AU - Engelborghs, S.

AU - de Roeck, E.

AU - Martinez-Lage, P.

AU - Altuna, M.

AU - Tainta, M.

AU - Lleó, Alberto

AU - Sala, Isabel

AU - Popp, J.

AU - Peyratout, G.

AU - Winchester, L.

AU - Nevado-Holgado, A.

AU - Verhey, F.

AU - Tsolaki, M.

AU - Andreasson, U.

AU - Blennow, K.

AU - Zetterberg, H.

AU - Streffer, J.

AU - Vos, S.J.B.

AU - Lovestone, S.

AU - Visser, P.J.

AU - Bertram, L.

AU - Lunnon, K.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - Alzheimer's disease (AD)

KW - DNA methylation

KW - YKL‐40

KW - amyloid

KW - biomarker

KW - blood

KW - cerebrospinal fluid (CSF)

KW - epigenetics

KW - epigenome‐wide association study (EWAS)

KW - genome‐wide association study (GWAS)

KW - methylation quantitative trait loci (mQTL)

KW - mild cognitive impairment (MCI)

KW - neurofilament light (NfL)

KW - protein quantitative trait loci (pQTL)

KW - tau

U2 - 10.1002/alz.14098

DO - 10.1002/alz.14098

M3 - Article

C2 - 39193893

SN - 1552-5279

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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