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 Robertson; Rosie M. Walker; Robert I. McGeachan; Archie Campbell; Xueyi Shen; 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 J. 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 Robertson, Rosie M. Walker, Robert I. McGeachan, Archie Campbell, Xueyi Shen, 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 J. Nevado-Holgado, Tamir Chandra, Caroline Hayward, Kathryn L. Evans, David J. Porteous, Simon R. Cox, Heather C. Whalley, Andrew M. McIntosh, Riccardo E. Marioni (Lead / Corresponding author)

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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.

Original language	English
Article number	4670
Number of pages	14
Journal	Nature Communications
Volume	13
DOIs	https://doi.org/10.1038/s41467-022-32319-8
Publication status	Published - 9 Aug 2022

Keywords

Cognitive ageing
DNA methylation
Epigenomics
Predictive markers

ASJC Scopus subject areas

General
General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

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10.1038/s41467-022-32319-8Licence: CC BY

Final Published VersionFinal published version, 2.55 MBLicence: CC BY

Cite this

Gadd, D. A., Hillary, R. F., McCartney, D. L., Shi, L., Stolicyn, A., Robertson, N., Walker, R. M., McGeachan, R. I., Campbell, A., Shen, X., 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, Article 4670. https://doi.org/10.1038/s41467-022-32319-8

@article{88783cf2c92144a2a73516f11540b40e,

title = "Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health",

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.",

keywords = "Cognitive ageing, DNA methylation, Epigenomics, Predictive markers",

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

note = "Funding: MRC grants MR/S010351/1, MR/W002566/1 and MR/W002388/1",

year = "2022",

month = aug,

day = "9",

doi = "10.1038/s41467-022-32319-8",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Gadd, DA, Hillary, RF, McCartney, DL, Shi, L, Stolicyn, A, Robertson, N, Walker, RM, McGeachan, RI, Campbell, A, Shen, X, Barbu, MC, Green, C, Morris, SW, Harris, MA, Backhouse, EV, Wardlaw, JM, Steele, JD, Oyarzún, DA, Muniz-Terrera, G, Ritchie, C, Nevado-Holgado, AJ, 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, 4670. https://doi.org/10.1038/s41467-022-32319-8

TY - JOUR

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

AU - Walker, Rosie M.

AU - McGeachan, Robert I.

AU - Campbell, Archie

AU - Shen, Xueyi

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 J.

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.

N1 - Funding: MRC grants MR/S010351/1, MR/W002566/1 and MR/W002388/1

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 - Cognitive ageing

KW - DNA methylation

KW - Epigenomics

KW - Predictive markers

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U2 - 10.1038/s41467-022-32319-8

DO - 10.1038/s41467-022-32319-8

M3 - Article

C2 - 35945220

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

M1 - 4670

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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Partnership for Assessment and Investigation of Neuropathic Pain: Studies Tracking Outcomes, Risks and Mechanisms (PAINSTORM) - (Joint with Universities of Oxford, Ghent and Aberdeen, Imperial College London and King's College London) (Advanced Pain Discovery Platform)

Consortium Against Pain InEquality (CAPE) - The Impact of Adverse Childhood Experiences on Chronic Pain and Responses to Treatment (Joint with University of Aberdeen, University of Edinburgh, University of Stirling and University College, London) (Advanced Pain Discovery Platform)

MICA: InterdisciPlInary Collaboration for EfficienT and Effective Use of Clinical Images in Big Data Health Care RESearch: PICTURES (Programme Grant) (Joint with Universities of Edinburgh and Abertay)

Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study: A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Partnership for Assessment and Investigation of Neuropathic Pain: Studies Tracking Outcomes, Risks and Mechanisms (PAINSTORM) - (Joint with Universities of Oxford, Ghent and Aberdeen, Imperial College London and King's College London) (Advanced Pain Discovery Platform)

Consortium Against Pain InEquality (CAPE) - The Impact of Adverse Childhood Experiences on Chronic Pain and Responses to Treatment (Joint with University of Aberdeen, University of Edinburgh, University of Stirling and University College, London) (Advanced Pain Discovery Platform)

MICA: InterdisciPlInary Collaboration for EfficienT and Effective Use of Clinical Images in Big Data Health Care RESearch: PICTURES (Programme Grant) (Joint with Universities of Edinburgh and Abertay)

Research output

Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study: A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments

Cite this