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

Hillary, Robert F.; Gadd, Danni A.; McCartney, Daniel L.; Shi, Liu; Campbell, Archie; Walker, Rosie M.; Ritchie, Craig W.; Deary, Ian J.; Evans, Kathryn L.; Nevado‐Holgado, Alejo J.; Hayward, Caroline; Porteous, David J.; McIntosh, Andrew M.; Lovestone, Simon; Robinson, Matthew Richard; Marioni, Riccardo E.

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

Hillary RF, Gadd DA, McCartney DL, Shi L, Campbell A, Walker RM, Ritchie CW, 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. 14(1), e12280.

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DOI

10.1002/dad2.12280

Journal Article | Published | English

Scopus indexed

Author

Hillary, Robert F.; Gadd, Danni A.; McCartney, Daniel L.; Shi, Liu; Campbell, Archie; Walker, Rosie M.; Ritchie, Craig W.; Deary, Ian J.; Evans, Kathryn L.; Nevado‐Holgado, Alejo J.; Hayward, Caroline; Porteous, David J.
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Department

Robinson Group

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 (nindividuals ≤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.

Publishing Year

2022

Date Published

2022-04-20

Journal Title

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

Acknowledgement

This research was funded in whole, or in part, by Wellcome [108890/Z/15/Z, 104036/Z/14/Z]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The authors are grateful to the families who took part in this study, the general practitioners, and the Scottish School of Primary Care for their help in recruiting them and the wider Generation Scotland team. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping and DNA methylation profiling of the Generation Scotland samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the Medical Research Council (MRC) UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” ([STRADL] Reference [104036/Z/14/Z]). Andrew M. McIntosh is supported by Wellcome [104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z], United Kingdom Research and Innovation (UKRI) MRC [MC_PC_17209, MR/S035818/1] and the European Union H2020 [SEP-210574971]. Ian J. Deary received support from Age UK, Wellcome, and the Medical Research Council. David J. Porteous is supported by Wellcome as prinicpal investigator (PI), and MRC and National Institute for Health Research (NIHR) grants as co-PI, made to the University of Edinburgh. Robert F. Hillary and Danni A. Gadd are supported by funding from the Wellcome 4-year PhD in Translational Neuroscience—training the next generation of basic neuroscientists to embrace clinical research [108890/Z/15/Z]. Daniel L. McCartney and Riccardo E. Marioni are supported by Alzheimer's Research UK major project grant ARUK-PG2017B-10. Riccardo E. Marioni is supported by Alzheimer's Society major project grant AS-PG-19b-010. Proteomic analyses in STRADL were supported by Dementias Platform UK (DPUK). DPUK funded this work through core grant support from the Medical Research Council [MR/L023784/2]. Kathryn L. Evans was supported by a grant from Alzheimer's Research UK, paid to the University of Edinburgh. Alejo J. Nevado-Holgado was funded by a Horizon 2020 Virtual Brain Cloud project (H2020-SC1-DTH-2018-1), in addition to funding from the MRC, UK Rosetrees, and King Abdullah University of Science and Technology, Saudi Arabia. Caroline Hayward is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease). Liu Shi is funded by DPUK through MRC [MR/L023784/2] and the UK Medical Research Council Award to the University of Oxford [MC_PC_17215]. Liu Shi received support from the NIHR Biomedical Research Centre at Oxford Health NHS Foundation Trust. Matthew R. Robinson is funded by a Swiss National Science Foundation Eccellenza Grant [PCEGP3-181181].

Volume

Issue

Article Number

e12280

eISSN

2352-8729

IST-REx-ID

17076

Cite this

Hillary RF, Gadd DA, McCartney DL, et al. 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. 2022;14(1). doi:10.1002/dad2.12280

Hillary, R. F., Gadd, D. A., McCartney, D. L., Shi, L., Campbell, A., Walker, R. M., … 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. Wiley. https://doi.org/10.1002/dad2.12280

Hillary, Robert F., Danni A. Gadd, Daniel L. McCartney, Liu Shi, Archie Campbell, Rosie M. Walker, Craig W. Ritchie, et al. “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. Wiley, 2022. https://doi.org/10.1002/dad2.12280.

R. F. Hillary et al., “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. Wiley, 2022.

Hillary, Robert F., et al. “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, Wiley, 2022, doi:10.1002/dad2.12280.

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