Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Danni A Gadd; Robert F Hillary; Daniel L McCartney; Liu Shi; Aleks Stolicyn; Neil A Robertson; Rosie M Walker; Robert I McGeachan; Archie Campbell; Shen Xueyi; Miruna C Barbu; Claire Green; Stewart W Morris; Mathew A Harris; Ellen V Backhouse; Joanna M Wardlaw; J Douglas Steele; Diego A Oyarzún; Graciela Muniz-Terrera; Craig Ritchie; Alejo Nevado-Holgado; Tamir Chandra; Caroline Hayward; Kathryn L Evans; David J Porteous; Simon R Cox; Heather C Whalley; Andrew M McIntosh; Riccardo E Marioni

doi:10.1038/s41467-022-32319-8

Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Danni A Gadd, Robert F Hillary, Daniel L McCartney, Liu Shi, Aleks Stolicyn, Neil A Robertson, Rosie M Walker, Robert I McGeachan, Archie Campbell, Shen Xueyi, Miruna C Barbu, Claire Green, Stewart W Morris, Mathew A Harris, Ellen V Backhouse, Joanna M Wardlaw, J Douglas Steele, Diego A Oyarzún, Graciela Muniz-Terrera, Craig RitchieAlejo Nevado-Holgado, Tamir Chandra, Caroline Hayward, Kathryn L Evans, David J Porteous, Simon R Cox, Heather C Whalley, Andrew M McIntosh, Riccardo E Marioni

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

Abstract

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.

Original language	English
Pages (from-to)	4670
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32319-8
Publication status	Published - 9 Aug 2022

Keywords / Materials (for Non-textual outputs)

Biomarkers/metabolism
Brain/metabolism
CpG Islands/genetics
DNA Methylation/genetics
Epigenome
Genome-Wide Association Study
Proteome/genetics
Proteomics

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OA_s41467-022-32319-8
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Final published version, 2.55 MBLicence: Creative Commons: Attribution (CC-BY)

Omics prediction of Alzheimer's disease
Marioni, R. (Principal Investigator)
UK-based charities
1/10/17 → 31/01/21
Project: Research

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Gadd, D. A., Hillary, R. F., McCartney, D. L., Shi, L., Stolicyn, A., Robertson, N. A., Walker, R. M., McGeachan, R. I., Campbell, A., Xueyi, S., Barbu, M. C., Green, C., Morris, S. W., Harris, M. A., Backhouse, E. V., Wardlaw, J. M., Steele, J. D., Oyarzún, D. A., Muniz-Terrera, G., ... Marioni, R. E. (2022). Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health. Nature Communications, 13(1), 4670. https://doi.org/10.1038/s41467-022-32319-8

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abstract = "Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.",

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Gadd, DA, Hillary, RF , McCartney, DL, Shi, L, Stolicyn, A, Robertson, NA, Walker, RM, McGeachan, RI, Campbell, A, Xueyi, S, Barbu, MC, Green, C, Morris, SW, Harris, MA, Backhouse, EV, Wardlaw, JM, Steele, JD, Oyarzún, DA , Muniz-Terrera, G , Ritchie, C, Nevado-Holgado, A, Chandra, T , Hayward, C , Evans, KL, Porteous, DJ, Cox, SR , Whalley, HC , McIntosh, AM & Marioni, RE 2022, 'Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health', Nature Communications, vol. 13, no. 1, pp. 4670. https://doi.org/10.1038/s41467-022-32319-8

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T1 - Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

AU - Gadd, Danni A

AU - Hillary, Robert F

AU - McCartney, Daniel L

AU - Shi, Liu

AU - Stolicyn, Aleks

AU - Robertson, Neil A

AU - Walker, Rosie M

AU - McGeachan, Robert I

AU - Campbell, Archie

AU - Xueyi, Shen

AU - Barbu, Miruna C

AU - Green, Claire

AU - Morris, Stewart W

AU - Harris, Mathew A

AU - Backhouse, Ellen V

AU - Wardlaw, Joanna M

AU - Steele, J Douglas

AU - Oyarzún, Diego A

AU - Muniz-Terrera, Graciela

AU - Ritchie, Craig

AU - Nevado-Holgado, Alejo

AU - Chandra, Tamir

AU - Hayward, Caroline

AU - Evans, Kathryn L

AU - Porteous, David J

AU - Cox, Simon R

AU - Whalley, Heather C

AU - McIntosh, Andrew M

AU - Marioni, Riccardo E

PY - 2022/8/9

Y1 - 2022/8/9

N2 - Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.

AB - Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.

KW - Biomarkers/metabolism

KW - Brain/metabolism

KW - CpG Islands/genetics

KW - DNA Methylation/genetics

KW - Epigenome

KW - Genome-Wide Association Study

KW - Proteome/genetics

KW - Proteomics

U2 - 10.1038/s41467-022-32319-8

DO - 10.1038/s41467-022-32319-8

M3 - Article

C2 - 35945220

SN - 2041-1723

VL - 13

SP - 4670

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

Omics prediction of Alzheimer's disease

Cite this