Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer’s disease implicate TBCA and TREM2 in disease risk

Robert Hillary; Danni Gadd; Daniel L McCartney; Liu Shi; Archie Campbell; Rosie Walker; Craig Ritchie; Ian J Deary; Kathryn Louise Evans; Alejo J Nevado-Holgado; Caroline Hayward; David John Porteous; Andrew M McIntosh; Simon  Lovestone; Matthew R. Robinson; Riccardo E Marioni

doi:10.1002/dad2.12280

Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer’s disease implicate TBCA and TREM2 in disease risk

Robert Hillary, Danni Gadd, Daniel L McCartney, Liu Shi, Archie Campbell, Rosie Walker, Craig Ritchie, Ian J Deary, Kathryn Louise Evans, Alejo J Nevado-Holgado, Caroline Hayward, David John Porteous, Andrew M McIntosh, Simon Lovestone, Matthew R. Robinson, Riccardo E Marioni

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

Abstract / Description of output

Introduction: The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms.

Methods: Genome-wide and epigenome-wide studies (n individuals ≤1064) were performed on plasma levels of 282 AD-associated proteins, identified by a structured literature review. Bayesian penalized regression estimated contributions of genetic and epigenetic variation toward inter-individual differences in plasma protein levels. Mendelian randomization (MR) and co-localization tested associations between proteins and disease-related phenotypes.

Results: Sixty-four independent genetic and 26 epigenetic loci were associated with 45 proteins. Novel findings included an association between plasma triggering receptor expressed on myeloid cells 2 (TREM2) levels and a polymorphism and cytosine-phosphate-guanine (CpG) site within the MS4A4A locus. Higher plasma tubulin-specific chaperone A (TBCA) and TREM2 levels were significantly associated with lower AD risk.

Discussion: Our data inform the regulation of biomarker levels and their relationships with AD.

Original language	English
Article number	e12280
Journal	Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Volume	14
Issue number	1
DOIs	https://doi.org/10.1002/dad2.12280
Publication status	Published - 20 Apr 2022

Access to Document

10.1002/dad2.12280Licence: Creative Commons: Attribution (CC-BY)

OA_DAD2-14-e12280Final published version, 990 KBLicence: Creative Commons: Attribution (CC-BY)

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12280Licence: Creative Commons: Attribution (CC-BY)

2 Active
3 Finished

Exploiting genomic approaches to identify the environmental basis of depression
McIntosh, A.
UK-based charities
1/06/21 → 31/05/26
Project: Research
Generation Scotland: NextGenScot
Porteous, D., Deary, I., Hayward, C., McIntosh, A. & Sudlow, C.
UK-based charities
1/11/19 → 31/10/24
Project: Research
Omics prediction of Alzheimer's disease
Marioni, R.
UK-based charities
1/10/17 → 31/01/21
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

Cite this

Hillary, R., Gadd, D., McCartney, D. L., Shi, L., Campbell, A., Walker, R., Ritchie, C., Deary, I. J., Evans, K. L., Nevado-Holgado, A. J., Hayward, C., Porteous, D. J., McIntosh, A. M., Lovestone, S., Robinson, M. R., & Marioni, R. E. (2022). Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer’s disease implicate TBCA and TREM2 in disease risk. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 14(1), Article e12280. https://doi.org/10.1002/dad2.12280

@article{72f24e95bf184b16bc6a355fe541f1ec,

title = "Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer{\textquoteright}s disease implicate TBCA and TREM2 in disease risk",

abstract = "Introduction: The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms.Methods: Genome-wide and epigenome-wide studies (n individuals ≤1064) were performed on plasma levels of 282 AD-associated proteins, identified by a structured literature review. Bayesian penalized regression estimated contributions of genetic and epigenetic variation toward inter-individual differences in plasma protein levels. Mendelian randomization (MR) and co-localization tested associations between proteins and disease-related phenotypes. Results: Sixty-four independent genetic and 26 epigenetic loci were associated with 45 proteins. Novel findings included an association between plasma triggering receptor expressed on myeloid cells 2 (TREM2) levels and a polymorphism and cytosine-phosphate-guanine (CpG) site within the MS4A4A locus. Higher plasma tubulin-specific chaperone A (TBCA) and TREM2 levels were significantly associated with lower AD risk. Discussion: Our data inform the regulation of biomarker levels and their relationships with AD.",

author = "Robert Hillary and Danni Gadd and McCartney, {Daniel L} and Liu Shi and Archie Campbell and Rosie Walker and Craig Ritchie and Deary, {Ian J} and Evans, {Kathryn Louise} and Nevado-Holgado, {Alejo J} and Caroline Hayward and Porteous, {David John} and McIntosh, {Andrew M} and Simon Lovestone and Robinson, {Matthew R.} and Marioni, {Riccardo E}",

note = "{\textcopyright} 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.",

year = "2022",

month = apr,

day = "20",

doi = "10.1002/dad2.12280",

language = "English",

volume = "14",

journal = "Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring",

issn = "2352-8729",

publisher = "Elsevier",

number = "1",

}

Hillary, R, Gadd, D, McCartney, DL, Shi, L, Campbell, A , Walker, R , Ritchie, C , Deary, IJ , Evans, KL, Nevado-Holgado, AJ, Hayward, C, Porteous, DJ, McIntosh, AM, Lovestone, S, Robinson, MR & Marioni, RE 2022, 'Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer’s disease implicate TBCA and TREM2 in disease risk', Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, vol. 14, no. 1, e12280. https://doi.org/10.1002/dad2.12280

TY - JOUR

T1 - Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer’s disease implicate TBCA and TREM2 in disease risk

AU - Hillary, Robert

AU - Gadd, Danni

AU - McCartney, Daniel L

AU - Shi, Liu

AU - Campbell, Archie

AU - Walker, Rosie

AU - Ritchie, Craig

AU - Deary, Ian J

AU - Evans, Kathryn Louise

AU - Nevado-Holgado, Alejo J

AU - Hayward, Caroline

AU - Porteous, David John

AU - McIntosh, Andrew M

AU - Lovestone, Simon

AU - Robinson, Matthew R.

AU - Marioni, Riccardo E

PY - 2022/4/20

Y1 - 2022/4/20

N2 - Introduction: The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms.Methods: Genome-wide and epigenome-wide studies (n individuals ≤1064) were performed on plasma levels of 282 AD-associated proteins, identified by a structured literature review. Bayesian penalized regression estimated contributions of genetic and epigenetic variation toward inter-individual differences in plasma protein levels. Mendelian randomization (MR) and co-localization tested associations between proteins and disease-related phenotypes. Results: Sixty-four independent genetic and 26 epigenetic loci were associated with 45 proteins. Novel findings included an association between plasma triggering receptor expressed on myeloid cells 2 (TREM2) levels and a polymorphism and cytosine-phosphate-guanine (CpG) site within the MS4A4A locus. Higher plasma tubulin-specific chaperone A (TBCA) and TREM2 levels were significantly associated with lower AD risk. Discussion: Our data inform the regulation of biomarker levels and their relationships with AD.

AB - Introduction: The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms.Methods: Genome-wide and epigenome-wide studies (n individuals ≤1064) were performed on plasma levels of 282 AD-associated proteins, identified by a structured literature review. Bayesian penalized regression estimated contributions of genetic and epigenetic variation toward inter-individual differences in plasma protein levels. Mendelian randomization (MR) and co-localization tested associations between proteins and disease-related phenotypes. Results: Sixty-four independent genetic and 26 epigenetic loci were associated with 45 proteins. Novel findings included an association between plasma triggering receptor expressed on myeloid cells 2 (TREM2) levels and a polymorphism and cytosine-phosphate-guanine (CpG) site within the MS4A4A locus. Higher plasma tubulin-specific chaperone A (TBCA) and TREM2 levels were significantly associated with lower AD risk. Discussion: Our data inform the regulation of biomarker levels and their relationships with AD.

U2 - 10.1002/dad2.12280

DO - 10.1002/dad2.12280

M3 - Article

C2 - 35475137

SN - 2352-8729

VL - 14

JO - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

JF - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

IS - 1

M1 - e12280

ER -

Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer’s disease implicate TBCA and TREM2 in disease risk

Abstract / Description of output

Access to Document

Fingerprint

Projects

Exploiting genomic approaches to identify the environmental basis of depression

Generation Scotland: NextGenScot

Omics prediction of Alzheimer's disease

Research output

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

Cite this