NMR metabolomics-guided DNA methylation mortality predictors

Daniele Bizzarri; Marcel J.T. Reinders; J. van Dongen; René Pool; Dorret I. Boomsma; A. H.M. Willemsen; Pieternella E. Slagboom; Erik B. van den Akker; BBMRI Consortium

doi:10.1016/j.ebiom.2024.105279

NMR metabolomics-guided DNA methylation mortality predictors

Daniele Bizzarri, Marcel J.T. Reinders, J. van Dongen, René Pool, Dorret I. Boomsma, A. H.M. Willemsen, Pieternella E. Slagboom, Erik B. van den Akker^*, BBMRI Consortium

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: ¹H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by ¹H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

Original language	English
Article number	105279
Journal	Ebiomedicine
Volume	107
DOIs	https://doi.org/10.1016/j.ebiom.2024.105279
Publication status	Published - Sept 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Funding

BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.This work was performed within the BBMRI Metabolomics Consortium funded by: BBMRI-NL (financed by NWO 184.021.007 and 184.033.111), X-omics (NWO 184.034.019), VOILA (ZonMW 457001001) and Medical Delta (METABODELTA: Metabolomics for clinical advances in the Medical Delta). EBvdA is funded by a personal grant of the Dutch Research Council (NWO; VENI: 09150161810095). Acknowledgements for all contributing studies can be found in the Supplementary Material-BIOS Consortium. Additional NTR samples were funded by the European Research Council (ERC-230374) project Genetics of Mental Illness (DIB).

Funders	Funder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	09150161810095
BBMRI-NL	184.034.019, 184.033.111, 184.021.007
European Research Council	ERC-230374
VOILA	ZonMW 457001001

Keywords

Ageing biomarkers
DNA methylation predictors
Epidemiology
Epigenetic clock
Metabolic risk score
NMR metabolomics

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10.1016/j.ebiom.2024.105279

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@article{4d3b5f8b10f04fd8975922a2d45edc76,

title = "NMR metabolomics-guided DNA methylation mortality predictors",

abstract = "Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.",

keywords = "Ageing biomarkers, DNA methylation predictors, Epidemiology, Epigenetic clock, Metabolic risk score, NMR metabolomics",

author = "Daniele Bizzarri and Reinders, {Marcel J.T.} and Lieke Kuiper and Marian Beekman and J. Deelen and {van Meurs}, {Joyce B.J.} and {van Dongen}, J. and Ren{\'e} Pool and Boomsma, {Dorret I.} and M. Ghanbari and Lude Franke and Geleijnse, {J. M.} and E. Boersma and {van Spil}, {W. E.} and {van Greevenbroek}, {M. M.J.} and Stehouwer, {C. D.A.} and {van der Kallen}, {C. J.H.} and Arts, {I. C.W.} and F. Rutters and Beulens, {J. W.J.} and M. Muilwijk and Elders, {P. J.M.} and {'t Hart}, {L. M.} and M. Ghanbari and Ikram, {M. A.} and Netea, {M. G.} and M. Kloppenburg and Ramos, {Y. F.M.} and N. Bomer and I. Meulenbelt and K. Stronks and Snijder, {M. B.} and Zwinderman, {A. H.} and Heijmans, {B. T.} and Lumey, {L. H.} and C. Wijmenga and J. Fu and A. Zhernakova and J. Deelen and Mooijaart, {S. P.} and M. Beekman and Slagboom, {P. E.} and Onderwater, {G. L.J.} and {van den Maagdenberg}, {A. M.J.M.} and Terwindt, {G. M.} and C. Thesing and M. Bot and Penninx, {B. W.J.H.} and S. Trompet and Jukema, {J. W.} and N. Sattar and {van der Horst}, {I. C.C.} and {van der Harst}, P. and C. So-Osman and {van Hilten}, {J. A.} and Nelissen, {R. G.H.H.} and H{\"o}fer, {I. E.} and Asselbergs, {F. W.} and P. Scheltens and Teunissen, {C. E.} and {van der Flier}, {W. M.} and {van Dongen}, J. and R. Pool and Willemsen, {A. H.M.} and Boomsma, {D. I.} and Suchiman, {H. E.D.} and {Barkey Wolf}, {J. J.H.} and D. Cats and H. Mei and M. Slofstra and M. Swertz and Reinders, {M. J.T.} and {van den Akker}, {Erik B.} and Slagboom, {Pieternella E.} and {van den Akker}, {Erik B.} and {BBMRI Consortium}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = sep,

doi = "10.1016/j.ebiom.2024.105279",

language = "English",

volume = "107",

journal = "Ebiomedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - NMR metabolomics-guided DNA methylation mortality predictors

AU - Bizzarri, Daniele

AU - Reinders, Marcel J.T.

AU - Kuiper, Lieke

AU - Beekman, Marian

AU - Deelen, J.

AU - van Meurs, Joyce B.J.

AU - van Dongen, J.

AU - Pool, René

AU - Boomsma, Dorret I.

AU - Ghanbari, M.

AU - Franke, Lude

AU - Geleijnse, J. M.

AU - Boersma, E.

AU - van Spil, W. E.

AU - van Greevenbroek, M. M.J.

AU - Stehouwer, C. D.A.

AU - van der Kallen, C. J.H.

AU - Arts, I. C.W.

AU - Rutters, F.

AU - Beulens, J. W.J.

AU - Muilwijk, M.

AU - Elders, P. J.M.

AU - 't Hart, L. M.

AU - Ghanbari, M.

AU - Ikram, M. A.

AU - Netea, M. G.

AU - Kloppenburg, M.

AU - Ramos, Y. F.M.

AU - Bomer, N.

AU - Meulenbelt, I.

AU - Stronks, K.

AU - Snijder, M. B.

AU - Zwinderman, A. H.

AU - Heijmans, B. T.

AU - Lumey, L. H.

AU - Wijmenga, C.

AU - Fu, J.

AU - Zhernakova, A.

AU - Deelen, J.

AU - Mooijaart, S. P.

AU - Beekman, M.

AU - Slagboom, P. E.

AU - Onderwater, G. L.J.

AU - van den Maagdenberg, A. M.J.M.

AU - Terwindt, G. M.

AU - Thesing, C.

AU - Bot, M.

AU - Penninx, B. W.J.H.

AU - Trompet, S.

AU - Jukema, J. W.

AU - Sattar, N.

AU - van der Horst, I. C.C.

AU - van der Harst, P.

AU - So-Osman, C.

AU - van Hilten, J. A.

AU - Nelissen, R. G.H.H.

AU - Höfer, I. E.

AU - Asselbergs, F. W.

AU - Scheltens, P.

AU - Teunissen, C. E.

AU - van der Flier, W. M.

AU - van Dongen, J.

AU - Pool, R.

AU - Willemsen, A. H.M.

AU - Boomsma, D. I.

AU - Suchiman, H. E.D.

AU - Barkey Wolf, J. J.H.

AU - Cats, D.

AU - Mei, H.

AU - Slofstra, M.

AU - Swertz, M.

AU - Reinders, M. J.T.

AU - van den Akker, Erik B.

AU - Slagboom, Pieternella E.

AU - van den Akker, Erik B.

AU - BBMRI Consortium

PY - 2024/9

Y1 - 2024/9

N2 - Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

AB - Background: 1H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals. Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by 1H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors. Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates. Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal. Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

KW - Ageing biomarkers

KW - DNA methylation predictors

KW - Epidemiology

KW - Epigenetic clock

KW - Metabolic risk score

KW - NMR metabolomics

UR - http://www.scopus.com/inward/record.url?scp=85201444255&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85201444255&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2024.105279

DO - 10.1016/j.ebiom.2024.105279

M3 - Article

AN - SCOPUS:85201444255

SN - 2352-3964

VL - 107

JO - Ebiomedicine

JF - Ebiomedicine

M1 - 105279

ER -

NMR metabolomics-guided DNA methylation mortality predictors

Abstract

Bibliographical note

Funding

Keywords

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