Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936

Robert Hillary; Daniel L McCartney; Sarah Harris; Anna Stevenson; Anne Seeboth; Qian Zhang; David Liewald; Kathryn L. Evans; Craig Ritchie; Elliot M Tucker-Drob; Naomi R Wray; Allan F. Mcrae; Peter M. Visscher; Ian Deary; Riccardo E. Marioni

doi:10.1038/s41467-019-11177-x

Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936

Robert Hillary, Daniel L McCartney, Sarah Harris, Anna Stevenson, Anne Seeboth, Qian Zhang, David Liewald, Kathryn L. Evans, Craig Ritchie, Elliot M Tucker-Drob, Naomi R Wray, Allan F. Mcrae, Peter M. Visscher, Ian Deary, Riccardo E. Marioni

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

Abstract

Although plasma proteins may serve as markers of neurological disease risk, the molecular mechanisms responsible for inter-individual variation in plasma protein levels are poorly understood. Therefore, we conduct genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n = 750 healthy older adults). We identify 41 independent genome-wide significant (P < 5.4 × 10−10) loci for 33 proteins and 26 epigenome-wide significant (P < 3.9 × 10−10) sites associated with the levels of 9 proteins. Using this information, we identify biological pathways in which putative neurological biomarkers are implicated (neurological, immunological and extracellular matrix metabolic pathways). We also observe causal relationships (by Mendelian randomisation analysis) between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels. Together, this may help inform causal relationships between biomarkers and neurological diseases.

Original language	English
Article number	3160
Journal	Nature Communications
Volume	10
Early online date	18 Jul 2019
DOIs	https://doi.org/10.1038/s41467-019-11177-x
Publication status	Published - Dec 2019

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HillaryEtalNC2019GenomeAndEpigenomeWideStudiesFinal published version, 877 KBLicence: Creative Commons: Attribution (CC-BY)

4 Finished

Omics prediction of Alzheimer's disease
Marioni, R. (Principal Investigator)
UK-based charities
1/10/17 → 31/01/21
Project: Research
The Disconnected Mind Phase 3
Cox, S. (Principal Investigator) & Deary, I. (Co-investigator)
1/04/16 → 31/03/23
Project: Research
RA2662 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Porteous, D. (Principal Investigator)
1/09/13 → 31/08/19
Project: Research

1 Doctoral Thesis

A multi–omics approach to understand the role of plasma proteins in cognitive ageing and dementia
Hillary, R., 2021
Research output: Thesis › Doctoral Thesis

Genetic and epigenetic architectures of neurological protein biomarkers in the Lothian Birth Cohort 1936 - EWAS
Wray, N. R. (Creator), Mcrae, A. F. (Creator), Visscher, P. (Creator), Deary, I. (Creator), Marioni, R. (Creator), Hillary, R. (Creator), Mccartney, D. (Creator), Harris, S. (Creator), Stevenson, A. (Creator), Seeboth, A. (Creator), Zhang, Q. (Creator), Liewald, D. (Creator), Evans, K. (Creator), Ritchie, C. (Creator) & Tucker-Drob, E. M. (Creator), Edinburgh DataShare, 18 Jul 2019
DOI: 10.7488/ds/2581
Dataset
Genetic and epigenetic architectures of neurological protein biomarkers in the Lothian Birth Cohort 1936 - GWAS Proteins
Hillary, R. (Creator), Mccartney, D. (Creator), Harris, S. (Creator), Wray, N. R. (Creator), Mcrae, A. F. (Creator), Visscher, P. (Creator), Stevenson, A. (Creator), Seeboth, A. (Creator), Zhang, Q. (Creator), Liewald, D. (Creator), Evans, K. (Creator), Tucker-Drob, E. M. (Creator), Ritchie, C. (Creator), Deary, I. (Creator) & Marioni, R. (Creator), Edinburgh DataShare, 18 Jul 2019
DOI: 10.7488/ds/2612
Dataset

Riccardo Marioni
Person: Academic: Research Active

Cite this

Hillary, R., McCartney, D. L., Harris, S., Stevenson, A., Seeboth, A., Zhang, Q., Liewald, D., Evans, K. L., Ritchie, C., Tucker-Drob, E. M., Wray, N. R., Mcrae, A. F., Visscher, P. M., Deary, I., & Marioni, R. E. (2019). Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936. Nature Communications, 10, Article 3160. https://doi.org/10.1038/s41467-019-11177-x

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title = "Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936",

abstract = "Although plasma proteins may serve as markers of neurological disease risk, the molecular mechanisms responsible for inter-individual variation in plasma protein levels are poorly understood. Therefore, we conduct genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n = 750 healthy older adults). We identify 41 independent genome-wide significant (P < 5.4 × 10−10) loci for 33 proteins and 26 epigenome-wide significant (P < 3.9 × 10−10) sites associated with the levels of 9 proteins. Using this information, we identify biological pathways in which putative neurological biomarkers are implicated (neurological, immunological and extracellular matrix metabolic pathways). We also observe causal relationships (by Mendelian randomisation analysis) between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels. Together, this may help inform causal relationships between biomarkers and neurological diseases.",

author = "Robert Hillary and McCartney, {Daniel L} and Sarah Harris and Anna Stevenson and Anne Seeboth and Qian Zhang and David Liewald and Evans, {Kathryn L.} and Craig Ritchie and Tucker-Drob, {Elliot M} and Wray, {Naomi R} and Mcrae, {Allan F.} and Visscher, {Peter M.} and Ian Deary and Marioni, {Riccardo E.}",

year = "2019",

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doi = "10.1038/s41467-019-11177-x",

language = "English",

volume = "10",

journal = "Nature Communications",

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Hillary, R , McCartney, DL , Harris, S, Stevenson, A, Seeboth, A, Zhang, Q, Liewald, D, Evans, KL , Ritchie, C, Tucker-Drob, EM, Wray, NR, Mcrae, AF, Visscher, PM, Deary, I & Marioni, RE 2019, 'Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936', Nature Communications, vol. 10, 3160. https://doi.org/10.1038/s41467-019-11177-x

TY - JOUR

T1 - Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936

AU - Hillary, Robert

AU - McCartney, Daniel L

AU - Harris, Sarah

AU - Stevenson, Anna

AU - Seeboth, Anne

AU - Zhang, Qian

AU - Liewald, David

AU - Evans, Kathryn L.

AU - Ritchie, Craig

AU - Tucker-Drob, Elliot M

AU - Wray, Naomi R

AU - Mcrae, Allan F.

AU - Visscher, Peter M.

AU - Deary, Ian

AU - Marioni, Riccardo E.

PY - 2019/12

Y1 - 2019/12

N2 - Although plasma proteins may serve as markers of neurological disease risk, the molecular mechanisms responsible for inter-individual variation in plasma protein levels are poorly understood. Therefore, we conduct genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n = 750 healthy older adults). We identify 41 independent genome-wide significant (P < 5.4 × 10−10) loci for 33 proteins and 26 epigenome-wide significant (P < 3.9 × 10−10) sites associated with the levels of 9 proteins. Using this information, we identify biological pathways in which putative neurological biomarkers are implicated (neurological, immunological and extracellular matrix metabolic pathways). We also observe causal relationships (by Mendelian randomisation analysis) between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels. Together, this may help inform causal relationships between biomarkers and neurological diseases.

AB - Although plasma proteins may serve as markers of neurological disease risk, the molecular mechanisms responsible for inter-individual variation in plasma protein levels are poorly understood. Therefore, we conduct genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n = 750 healthy older adults). We identify 41 independent genome-wide significant (P < 5.4 × 10−10) loci for 33 proteins and 26 epigenome-wide significant (P < 3.9 × 10−10) sites associated with the levels of 9 proteins. Using this information, we identify biological pathways in which putative neurological biomarkers are implicated (neurological, immunological and extracellular matrix metabolic pathways). We also observe causal relationships (by Mendelian randomisation analysis) between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels. Together, this may help inform causal relationships between biomarkers and neurological diseases.

U2 - 10.1038/s41467-019-11177-x

DO - 10.1038/s41467-019-11177-x

M3 - Article

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 3160

ER -

Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936

Abstract

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Projects

Omics prediction of Alzheimer's disease

The Disconnected Mind Phase 3

RA2662 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

Research output

A multi–omics approach to understand the role of plasma proteins in cognitive ageing and dementia

Datasets

Genetic and epigenetic architectures of neurological protein biomarkers in the Lothian Birth Cohort 1936 - EWAS

Genetic and epigenetic architectures of neurological protein biomarkers in the Lothian Birth Cohort 1936 - GWAS Proteins

Profiles

Riccardo Marioni

Cite this