DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain

Danni Gadd; Hannah Smith; Donncha Mullin; Ola Chybowska; Robert Hillary; Dorien M Kimenai; Elena Bernabeu; Yipeng Cheng; Chloe Fawns-Ritchie; Archie Campbell; Danielle Page; Adele Taylor; Janie Corley; Maria C Valdés Hernández; Susana Muñoz Maniega; Mark E Bastin; Joanna M. Wardlaw; Rosie Walker; Kathryn Louise Evans; Andrew M. McIntosh; Caroline Hayward; Tom C. Russ; Sarah E. Harris; Paul Welsh; Naveed Sattar; Simon R. Cox; Daniel L McCartney; Riccardo E Marioni

doi:10.1186/s13148-024-01734-7

DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain

Danni Gadd, Hannah Smith, Donncha Mullin, Ola Chybowska, Robert Hillary, Dorien M Kimenai, Elena Bernabeu, Yipeng Cheng, Chloe Fawns-Ritchie, Archie Campbell, Danielle Page, Adele Taylor, Janie Corley, Maria C Valdés Hernández, Susana Muñoz Maniega, Mark E Bastin, Joanna M. Wardlaw, Rosie Walker, Kathryn Louise Evans, Andrew M. McIntoshCaroline Hayward, Tom C. Russ, Sarah E. Harris, Paul Welsh, Naveed Sattar, Simon R. Cox, Daniel L McCartney, Riccardo E Marioni^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Plasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. Results: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all P _FDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, P _FDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R ² range of 5.7–12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population. Conclusions: EpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.

Original language	English
Article number	124
Journal	Nature
Volume	16
DOIs	https://doi.org/10.1186/s13148-024-01734-7
Publication status	Published - 10 Sept 2024

Keywords / Materials (for Non-textual outputs)

GD15
NT-proBNP
epigenetic
DNA methylation
dementia
diabetes
cardiovascular
stroke
risk stratification
brain

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Gadd, D., Smith, H., Mullin, D., Chybowska, O., Hillary, R., Kimenai, D. M., Bernabeu, E., Cheng, Y., Fawns-Ritchie, C., Campbell, A., Page, D., Taylor, A., Corley, J., Valdés Hernández, M. C., Muñoz Maniega, S., Bastin, M. E., Wardlaw, J. M., Walker, R., Evans, K. L., ... Marioni, R. E. (2024). DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain. Nature, 16, Article 124. https://doi.org/10.1186/s13148-024-01734-7

@article{004a7b3bfea34cc5b92ac29d23c4591a,

title = "DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain",

abstract = "Background: Plasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. Results: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all P FDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, P FDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R 2 range of 5.7–12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population. Conclusions: EpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.",

keywords = "GD15, NT-proBNP, epigenetic, DNA methylation, dementia, diabetes, cardiovascular, stroke, risk stratification, brain",

author = "Danni Gadd and Hannah Smith and Donncha Mullin and Ola Chybowska and Robert Hillary and Kimenai, {Dorien M} and Elena Bernabeu and Yipeng Cheng and Chloe Fawns-Ritchie and Archie Campbell and Danielle Page and Adele Taylor and Janie Corley and {Vald{\'e}s Hern{\'a}ndez}, {Maria C} and {Mu{\~n}oz Maniega}, Susana and Bastin, {Mark E} and Wardlaw, {Joanna M.} and Rosie Walker and Evans, {Kathryn Louise} and McIntosh, {Andrew M.} and Caroline Hayward and Russ, {Tom C.} and Harris, {Sarah E.} and Paul Welsh and Naveed Sattar and Cox, {Simon R.} and McCartney, {Daniel L} and Marioni, {Riccardo E}",

year = "2024",

month = sep,

day = "10",

doi = "10.1186/s13148-024-01734-7",

language = "English",

volume = "16",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

}

Gadd, D, Smith, H, Mullin, D, Chybowska, O, Hillary, R , Kimenai, DM, Bernabeu, E, Cheng, Y, Fawns-Ritchie, C , Campbell, A, Page, D, Taylor, A, Corley, J , Valdés Hernández, MC , Muñoz Maniega, S , Bastin, ME , Wardlaw, JM, Walker, R, Evans, KL , McIntosh, AM , Hayward, C , Russ, TC , Harris, SE, Welsh, P, Sattar, N, Cox, SR , McCartney, DL & Marioni, RE 2024, 'DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain', Nature, vol. 16, 124. https://doi.org/10.1186/s13148-024-01734-7

TY - JOUR

T1 - DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain

AU - Gadd, Danni

AU - Smith, Hannah

AU - Mullin, Donncha

AU - Chybowska, Ola

AU - Hillary, Robert

AU - Kimenai, Dorien M

AU - Bernabeu, Elena

AU - Cheng, Yipeng

AU - Fawns-Ritchie, Chloe

AU - Campbell, Archie

AU - Page, Danielle

AU - Taylor, Adele

AU - Corley, Janie

AU - Valdés Hernández, Maria C

AU - Muñoz Maniega, Susana

AU - Bastin, Mark E

AU - Wardlaw, Joanna M.

AU - Walker, Rosie

AU - Evans, Kathryn Louise

AU - McIntosh, Andrew M.

AU - Hayward, Caroline

AU - Russ, Tom C.

AU - Harris, Sarah E.

AU - Welsh, Paul

AU - Sattar, Naveed

AU - Cox, Simon R.

AU - McCartney, Daniel L

AU - Marioni, Riccardo E

PY - 2024/9/10

Y1 - 2024/9/10

N2 - Background: Plasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. Results: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all P FDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, P FDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R 2 range of 5.7–12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population. Conclusions: EpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.

AB - Background: Plasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. Results: In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all P FDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, P FDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R 2 range of 5.7–12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population. Conclusions: EpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.

KW - GD15

KW - NT-proBNP

KW - epigenetic

KW - DNA methylation

KW - dementia

KW - diabetes

KW - cardiovascular

KW - stroke

KW - risk stratification

KW - brain

U2 - 10.1186/s13148-024-01734-7

DO - 10.1186/s13148-024-01734-7

M3 - Article

SN - 0028-0836

VL - 16

JO - Nature

JF - Nature

M1 - 124

ER -

DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain

Abstract

Keywords / Materials (for Non-textual outputs)

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