Marioni, Riccardo

Ritchie, Craig

Evans, Kathy

Deary, Ian

Hillary, Robert Francis

Biotechnology and Biological Sciences Research Council (BBSRC)

2022-03-08T15:36:03Z

2022-03-08T15:36:03Z

2021-12-17

The global burden of age-related cognitive decline and dementia will continue to rise in tandem with our ageing population. This necessitates the discovery of novel biomarkers and candidate drug targets to combat cognitive dysfunction. Blood proteins are important drug targets, and blood samples can be acquired routinely in clinical settings and epidemiological studies. Whereas hundreds of blood proteins are associated with cognitive ability and dementia, we do not understand whether these associations represent correlation or causation. Genome-wide association studies (GWAS) are required to define variants that are associated with blood protein levels. These variants can proxy for candidate disease-markers and assess their causal associations with health outcomes in analysis methods such as Mendelian randomisation. DNA methylation is an epigenetic mechanism that regulates gene expression and is influenced by genetic and environmental factors. Studying the relationship between DNA methylation and protein levels could reveal whether genetic variation or environmental factors likely mediate associations between blood proteins and disease states. The first aim of this thesis is to conduct GWAS and epigenome-wide association studies (EWAS, using DNA methylation) on plasma levels of 422 unique proteins. Using these data, I apply causal inference approaches to determine whether blood proteins are causally associated with Alzheimer’s disease risk. Several strategies have been proposed to estimate biological age by leveraging inter-individual variation in DNA methylation profiles. Epigenetic measures of ageing correlate strongly with chronological age. Recently, a novel epigenetic measure of ageing termed ‘DNAm GrimAge’ was developed to predict one’s risk of mortality. DNAm GrimAge is a composite biomarker that incorporates methylation-based predictors of seven blood protein levels and smoking. The relationship between this biomarker of ageing and cognitive decline or dementia is not known. Therefore, the second aim of this thesis is to examine whether DNAm GrimAge associates with measures of brain health and Alzheimer’s disease. To conduct these aims, I utilise data from two cohort studies: the Lothian Birth Cohort 1936 (n ≤ 906, LBC1936) and Generation Scotland (n ≤ 9,537, GS). In Chapters 1-3, I provide an overview of cognitive ageing and dementia. I describe GWAS and EWAS on blood protein levels and the development of DNAm GrimAge. In Chapter 4, I detail the population cohorts and main methodologies that are used in this thesis. In Chapter 5, I conduct GWAS and EWAS on plasma levels of 92 neurology-related proteins (n ≤ 750, LBC1936). I identified 41 independent genetic and 26 epigenetic loci that associate with 33 and 9 proteins, respectively. I showed that an immune-related protein, poliovirus receptor (PVR), is causally associated with Alzheimer’s disease risk. In Chapter 6, I use a novel Bayesian framework termed BayesR+ to perform an integrated GWAS/EWAS on plasma levels of 70 inflammation-associated proteins (n = 876, LBC1936). Many GWAS and EWAS use linear models, which examine every measured genetic or epigenetic site in isolation. BayesR+ accounts for intercorrelations among genetic and epigenetic sites and the reciprocal influences of these data types. I estimated the contribution of genetic and epigenetic variation towards inter-individual differences in inflammatory protein levels, considered alone and together. There was no evidence for causal associations between blood inflammatory proteins and the risk of Alzheimer’s disease. In Chapter 7, I perform a systematic literature review to identify known blood protein correlates of Alzheimer’s disease. I then use BayesR+ to conduct an integrated GWAS and EWAS on plasma levels of 282 Alzheimer’s disease-associated proteins (n ≤ 1,064, GS). I observed strong evidence for causal associations between two proteins, TBCA and TREM2, and Alzheimer’s disease risk. In Chapter 8, I examine associations between DNAm GrimAge and measures of brain health (n ≤ 709, LBC1936). A higher-than-expected DNAm GrimAge associated with poorer performance on cognitive tasks and neurostructural correlates of dementia at age 73. I observed weak evidence to suggest that DNAm GrimAge assessed at age 70 predicts cognitive decline up to age 79. In Chapter 9, I assess whether DNAm GrimAge and other measures of epigenetic ageing predict the prevalence and incidence of common disease states, including Alzheimer’s disease (n ≤ 9,537, GS). Epigenetic ageing measures did not predict the prevalence or incidence of Alzheimer’s disease. In Chapter 10, I discuss the major findings from this thesis in light of their limitations. The work presented in this thesis helps to detail the molecular regulation of 422 plasma protein levels and their causal associations with Alzheimer’s disease. This work also highlights the performance of DNAm GrimAge in predicting indices of cognitive performance and common disease states. By incorporating genetic, epigenetic and protein data in two large-scale epidemiological studies, my findings inform our understanding of relationships between blood proteins and cognitive ageing and dementia.

https://hdl.handle.net/1842/38672

http://dx.doi.org/10.7488/era/1930

en

The University of Edinburgh

Hillary RF, Marioni RE. MethylDetectR - a software for methylation-based health profiling. Wellcome Open Research. 2020; 5:283

Hillary RF, Stevenson AJ, McCartney DL, Campbell A, Walker RM, Howard DM, Ritchie CW, Horvath S, Hayward C, 4 authors, Marioni RE. Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden. Clinical Epigenetics. 2020; 12(1):115

Hillary RF, Trejo-Banos D, Kousathanas A, McCartney DL, Harris SE, Stevenson AJ, Patxot M, Ojavee SE, Zhang Q, 9 authors, Marioni RE. Multi-method genome and epigenome wide studies of inflammatory protein levels in healthy older adults. Genome Medicine. 2020; 12(1):60

Hillary RF*, Stevenson AJ*, Cox SR, McCartney DL, Harris SE, Seeboth A, Higham J, Sproul D, Taylor AM, 13 authors, Marioni RE. An epigenetic predictor of death captures multi-modal measures of brain health. Molecular Psychiatry. 2019; no pagination

Hillary RF, McCartney DL, Harris SE, Stevenson AJ, Seeboth A, Zhang Q, Liewald DC, Evans KL, Ritchie CW, 5 authors, Marioni RE. Genome and epigenome wide studies of neurological protein biomarkers in the Lothian Birth Cohort 1936. Nature Communications. 2019; 10(1):3160

McCartney DL*, Hillary RF*, Stevenson AJ, Ritchie SJ, Walker RM, Zhang Q, Morris SW, Bermingham ML, Campbell A, 11 authors, Marioni RE. Epigenetic prediction of complex traits and death. Genome Biology. 2018; 19, 1:136

Hillary RF, FitzGerald U. A lifetime of stress: ATF6 in development and homeostasis. Journal of Biomedical Science. 2018; 25, 1:48

Gadd DA*, Hillary RF*, McCartney DL*, Zaghlool S*, Stevenson AJ, Nangle C, Campbell A, Flaig R, Harris SE, 17 authors, Marioni RE. Epigenetic scores for the circulating proteome as tools for disease prediction. bioRxiv. 2020; doi.org/10.1101/2020.12.01.404681

Hillary RF, Gadd DA, McCartney DL, Shi L, Campbell A, Walker RM, Ritchie CW, Deary IJ, Evans KL, 6 authors, Marioni RE. Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer’s disease implicate TBCA and TREM2 in disease risk. medRxiv. 2021; doi.org/10.1101/2021.06.07.21258457.

Fetit R, Hillary RF, Price DJ, Lawrie SM. The Neuropathology of Autism: A Systematic Review of Post-Mortem Studies of Autism and Related Disorders. Neuroscience and Biobehavioral Reviews. 2021; S0149-7634(21)00313-4.

Nabais MF, Laws SM, Tin L, Vallerga CL, Armstong NJ, Blair IP, Kwok JB, Mather KA, Mellick GD, 44 authors, Hillary RF, 17 authors. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders. Genome Biology. 2021; 26, 22:90

Gadd DA, Stevenson AJ, Hillary RF, McCartney DL, Wrobel N, McCaffety S, Murphy L, Russ TC, Harris SE, 7 authors, Marioni RE. Epigenetic predictors of lifestyle traits applied to the blood and brain. Brain Communications. 2021; 19, 3(2)

Stevenson AJ, Gadd DA, Hillary RF, McCartney DL, Campbell A, Walker RM, Evans KL, Harris SE, Spires-Jones TL, 4 authors, Marioni RE. Creating and validating a DNA methylation-based proxy for interleukin-6. The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences. 2021; glab046

Green C, Shen X, Stevenson AJ, Conole ELS, Harris MA, Barbu MC, Hawkins EL, Adams MJ, Hillary RF, 14 authors, Whalley HC. Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder. Brain, Behavior and Immunity. 2020; no pagination

Madden RA, McCartney DL, Walker RM, Hillary RF, Bermingham ML, Rawlik K, Morris SW, Campbell A, Porteous DJ, 4 authors, Marioni RE. Birth weight associations with DNA methylation differences in an adult population. Epigenetics. 2020; 1-14

Stevenson AJ, McCartney DL, Hillary RF, Campbell A, Morris SW, Bermingham ML, Walker RM, Evans KL, Boutin TS, 6 authors, Marioni RE. Characterisation of an inflammation-related epigenetic score and its association with cognitive ability. Clinical Epigenetics. 2020; 12, 1:113

Seeboth A, McCartney DL, Wang Y, Hillary RF, Stevenson AJ, Walker RM, Campbell A, Evans KL, McIntosh AM, 2 authors, Marioni RE. DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936. Clinical Epigenetics. 2020; 12, 1:49

McCartney DL, Zhang F, Hillary RF, Zhang Q, Stevenson AJ, Walker RM, Bermingham ML, Boutin T, Morris SW, 12 authors, Marioni RE. An epigenome-wide association study of sex-specific chronological ageing. Genome Medicine. 2019; 12, 1:1

Stevenson AJ, McCartney DL, Hillary RF, Redmond P, Taylor AM, Zhang Q, McRae AF, Spires-Jones TL, McIntosh AM, Deary IJ, Marioni RE. Childhood intelligence attenuates the association between biological ageing and health outcomes in later life. Translational Psychiatry. 2019; 9, 1:323

Gibson J, Russ TC, Clarke TK, Howard DM, Hillary RF, Evans KL, Walker RM, Bermingham ML, Morris SW, 8 authors, Marioni RE. A meta-analysis of genome-wide association studies of epigenetic age acceleration. PLoS Genetics. 2019; 15, 11:e1008104

Robertson NA, Hillary RF, McCartney DL, Terradas-Terradas M, Higham J, Sproul D, Deary IJ, Kirschner K, Marioni RE, Chandra T. Age-related clonal haemopoiesis is associated with increased epigenetic age. Current Biology. 2019; 29, 16:R786-R787

McCartney DL, Stevenson AJ, Hillary RF, Walker RM, Bermingham ML, Morris SW, Clarke TK, Campbell A, Murray AD, 6 authors, Marioni RE (2018). Epigenetic signatures of starting and stopping smoking. EBioMedicine. 2018; 37:214-220

Johnstone M, Hillary RF, St Clair D. Stem Cells to Inform the Neurobiology of Mental Illness. Current Topics in Behavioral Neuroscience. 2018; 40:13-43

McCartney DL, Hillary RF, Conole ELS, Trejo-Banos D, Gadd DA, Walker RM, Nangle C, Flaig R, Campbell A, 14 authors, Marioni RE. Blood-based epigenome-wide analyses of cognitive abilities. medRxiv. 2021; doi.org/10.1101/2021.05.24.21257698

Stevenson AJ, McCartney DL, Shireby GL, Hillary RF, King D, Tzioras M, Wrobel N, McCafferty S, Murphy L, 12 authors, Spires-Jones TL. A comparison of blood and brain-derived ageing and inflammation-related DNA methylation signatures and their association with microglial burdens. bioRxiv. 2020; doi.org/10.1101/2020.11.30.404228

ageing

proteomics

dementia

epigenomics

genomics

Multi-omics approach to understand the role of plasma proteins in cognitive ageing and dementia

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy