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• W4214752021 abstract "Article Figures and data Abstract Editor's evaluation eLife digest Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification. Editor's evaluation This is an important study that demonstrates the potential utility of the circulating proteome for disease prediction and risk stratification. https://doi.org/10.7554/eLife.71802.sa0 Decision letter eLife's review process eLife digest Although our genetic code does not change throughout our lives, our genes can be turned on and off as a result of epigenetics. Epigenetics can track how the environment and even certain behaviors add or remove small chemical markers to the DNA that makes up the genome. The type and location of these markers may affect whether genes are active or silent, this is, whether the protein coded for by that gene is being produced or not. One common epigenetic marker is known as DNA methylation. DNA methylation has been linked to the levels of a range of proteins in our cells and the risk people have of developing chronic diseases. Blood samples can be used to determine the epigenetic markers a person has on their genome and to study the abundance of many proteins. Gadd, Hillary, McCartney, Zaghlool et al. studied the relationships between DNA methylation and the abundance of 953 different proteins in blood samples from individuals in the German KORA cohort and the Scottish Lothian Birth Cohort 1936. They then used machine learning to analyze the relationship between epigenetic markers found in people’s blood and the abundance of proteins, obtaining epigenetic scores or ‘EpiScores’ for each protein. They found 109 proteins for which DNA methylation patterns explained between at least 1% and up to 58% of the variation in protein levels. Integrating the ‘EpiScores’ with 14 years of medical records for more than 9000 individuals from the Generation Scotland study revealed 137 connections between EpiScores for proteins and a future diagnosis of common adverse health outcomes. These included diabetes, stroke, depression, Alzheimer’s dementia, various cancers, and inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease. Age-related chronic diseases are a growing issue worldwide and place pressure on healthcare systems. They also severely reduce quality of life for individuals over many years. This work shows how epigenetic scores based on protein levels in the blood could predict a person’s risk of several of these diseases. In the case of type 2 diabetes, the EpiScore results replicated previous research linking protein levels in the blood to future diagnosis of diabetes. Protein EpiScores could therefore allow researchers to identify people with the highest risk of disease, making it possible to intervene early and prevent these people from developing chronic conditions as they age. Introduction Chronic morbidities place longstanding burdens on our health as we age. Stratifying an individual’s risk prior to symptom presentation is therefore critical (NHS England, 2016). Though complex morbidities are partially driven by genetic factors (Fuchsberger et al., 2016; Yao et al., 2018), epigenetic modifications have also been associated with disease (Lord and Cruchaga, 2014). DNA methylation (DNAm) encodes information on the epigenetic landscape of an individual and blood-based DNAm signatures have been found to predict all-cause mortality and disease onset, providing strong evidence to suggest that methylation is an important measure of disease risk (Hillary et al., 2020a; Lu et al., 2019; Zhang et al., 2017). DNAm can regulate gene transcription (Lea et al., 2018), and epigenetic differences can be reflected in the variability of the proteome (Hillary et al., 2019; Hillary et al., 2020b; Zaghlool et al., 2020). Low-grade inflammation, which is thought to exacerbate many age-related morbidities, is particularly well captured through DNAm studies of plasma protein levels (Zaghlool et al., 2020). As proteins are the primary effectors of disease, connecting the epigenome, proteome, and time to disease onset may help to resolve predictive biological signatures. Epigenetic predictors have utilised DNAm from the blood to estimate a person’s ‘biological age’ (Lu et al., 2019), measure their exposure to lifestyle and environmental factors (McCartney et al., 2018c; McCartney et al., 2018a; Peters et al., 2021), and predict circulating levels of inflammatory proteins (Stevenson et al., 2020; Stevenson et al., 2021). A leading epigenetic predictor of biological aging, the GrimAge epigenetic clock incorporates methylation scores for seven proteins along with smoking and chronological age, and is associated with numerous incident disease outcomes independently of smoking (Hillary et al., 2020a; Lu et al., 2019). This suggests there is predictive value gained in utilising DNAm scores relevant to protein levels as intermediaries for predictions. Methylation scores also point towards the pathways that may act on health beyond the protein biomarker that they are trained on. A portfolio of methylation scores for proteins across the circulating proteome could therefore aid in the prediction of disease and offer a different, but additive signal beyond methylation or protein data alone. Generation of an extensive range of epigenetic scores for protein levels has not been attempted to date. The capability of specific protein scores to predict a range of morbidities has also not been tested. However, DNAm scores for interleukin-6 (IL-6) and C-reactive protein (CRP) have been found to associate with a range of phenotypes independently of measured protein levels, show more stable longitudinal trajectories than repeated protein measurements, and, in some cases, outperform blood-based proteomic associations with brain morphology (Stevenson et al., 2021; Conole et al., 2021). This is likely due to DNAm representing the accumulation of more sustained effects over a longer period of time than protein measurements, which have often been shown to be variable in their levels when measured at multiple time points (Koenig et al., 2003; Liu et al., 2015; Moldoveanu et al., 2000; Shah et al., 2014). DNAm scores for proteins could therefore be used to alert clinicians to individuals with high-risk biological signatures, many years prior to disease onset. Here, we report a comprehensive association study of blood-based DNAm with proteomics and disease (Figure 1). We trained epigenetic scores – referred to as EpiScores – for 953 plasma proteins (with sample size ranging from 706 to 944 individuals) and validated them using two independent cohorts with 778 and 162 participants. We regressed out known genetic pQTL effects from the protein levels prior to generating the EpiScores to preclude the signatures being driven by common SNP data that are invariant across the lifespan. We then examined whether the most robust predictors (n = 109 EpiScores) associated with the incidence of 12 major morbidities (Table 1), over a follow-up period of up to 14 years in the Generation Scotland cohort (n = 9537). We also tested for associations between EpiScore levels and COVID-19 disease outcomes. We regressed out the effects of age on protein levels prior to training and testing; age was also included as a covariate in disease prediction models. We controlled for common risk factors for disease and assessed the capacity of EpiScores to identify previously reported protein-disease associations. Figure 1 Download asset Open asset EpiScores for plasma proteins as tools for disease prediction study design. DNA methylation scores were trained on 953 circulating plasma protein levels in the KORA and LBC1936 cohorts. There were 109 EpiScores selected based on performance (r > 0.1, p < 0.05) in independent test sets. The selected EpiScores were projected into Generation Scotland, a cohort that has extensive data linkage to GP and hospital records. We tested whether levels of each EpiScore at baseline could predict the onset of 12 leading causes of morbidity, over a follow-up period of up to 14 years; 137 EpiScore-disease associations were identified, for 11 morbidities. We then assessed whether EpiScore associations reflected protein associations for diabetes, which is a trait that has been well characterised using SOMAscan protein measurements. Of the 29 SOMAscan-derived EpiScore-diabetes associations, 23 highlighted previously reported protein-diabetes associations. Table 1 Incident morbidities in the Generation Scotland cohort. Counts are provided for the number of cases and controls for each incident trait in the basic and fully adjusted Cox models run in the Generation Scotland cohort (n = 9537). Mean time-to-event is summarised in years for each phenotype. Alzheimer’s dementia cases and controls were restricted to those older than 65 years. Breast cancer cases and controls were restricted to females. Basic modelFully adjusted modelMorbidityN casesN controlsYears to event(mean, SD)N casesN controlsYears to event(mean, SD)Rheumatoid arthritis6592816.1 (3.5)5477366.4 (3.3)Alzheimer’s dementia6937648.3 (2.7)5231378.2 (2.7)Bowel cancer7793986.4 (3.2)6578176.5 (3.2)Depression10183063.9 (3.3)8069763.7 (3.3)Breast cancer12953556 (3.4)11044015.9 (3.4)Lung cancer20192655.2 (3.1)17277055.1 (3.1)Inflammatory bowel disease20390835 (3.5)16375674.9 (3.5)Stroke31790236.5 (3.4)24875466.4 (3.5)COPD34689396.2 (3.4)27374596.1 (3.4)Ischaemic heart disease39586465.8 (3.3)30972485.9 (3.3)Diabetes42887565.7 (3.4)32273315.7 (3.4)Pain (back/neck)149453415.2 (3.5)122144755.3 (3.5) COPD: chronic obstructive pulmonary disease. A video summarising this study and detailing how the 109 EpiScores can be calculated in cohorts with DNAm data is available at: https://youtu.be/xKDWg0Wzvrg. Our MethylDetectR shiny app (Hillary and Marioni, 2020) has CpG weights for the 109 EpiScores integrated such that it automates the process of score generation for any DNAm dataset and is available at: https://www.ed.ac.uk/centre-genomic-medicine/research-groups/marioni-group/methyldetectr. A video on how to use the MethylDetectR shiny app to generate EpiScores is available at: https://youtu.be/65Y2Rv-4tPU. Results Selecting the most robust EpiScores for protein levels To generate epigenetic scores for a comprehensive set of plasma proteins, we ran elastic net penalised regression models using protein measurements from the SOMAscan (aptamer-based) and Olink (antibody-based) platforms. We used two cohorts: the German population-based study KORA (n = 944, mean age 59 years [SD 7.8], with 793 SOMAscan proteins) and the Scottish Lothian Birth Cohort 1936 (LBC1936) study (between 706 and 875 individuals in the training cohort, with a total of 160 Olink neurology and inflammatory panel proteins). The mean age of the LBC1936 participants at sampling was 70 (SD 0.8) for inflammatory and 73 (SD 0.7) for neurology proteins. Full demographic information is available for all cohorts in Supplementary file 1A. Prior to running the elastic net models, we rank-based inverse normalised protein levels and adjusted for age, sex, cohort-specific variables and, where present, cis and trans pQTL effects identified from previous analyses (Hillary et al., 2019; Hillary et al., 2020b; Suhre et al., 2017) (Materials and methods). Of a possible 793 proteins in KORA, 84 EpiScores had Pearson r > 0.1 and p < 0.05 when tested in an independent subset of Generation Scotland (The Stratifying Resilience and Depression Longitudinally [STRADL] study, n = 778) (Supplementary file 1B). These EpiScores were selected for EpiScore-disease analyses. Of the 160 Olink proteins trained in LBC1936, there were 21 with r > 0.1 and p < 0.05 in independent test sets (STRADL, n = 778, Lothian Birth Cohort 1921: LBC1921, n = 162) (Supplementary file 1C). Independent test set data were not available for four Olink proteins. However, they were included based on their performance (r > 0.1 and p < 0.05) in a holdout sample of 150 individuals who were left out of the training set. We then retrained all selected predictors on the full training samples. A total of 109 EpiScores (84 SOMAscan-based and 25 Olink-based) were brought forward (r > 0.1 and p < 0.05) to EpiScore-disease analyses (Figure 2 and Supplementary file 1D). There were five EpiScores for proteins common to both Olink and SOMAscan panels, which had variable correlation strength (GZMA r = 0.71, MMP.1 r = 0.46, CXCL10 r = 0.35, NTRK3 r = 0.26, and CXCL11 r = 0.09). Predictor weights, positional information, and cis/trans status for CpG sites contributing to these EpiScores are available in Supplementary file 1E. The number of CpG features selected for EpiScores ranged from 1 (lyzozyme) to 395 (aminoacylase-1 [ACY-1]), with a mean of 96 (Supplementary file 1F). The most frequently selected CpG was the smoking-related site cg05575921 (mapping to the AHRR gene), which was included in 25 EpiScores. Counts for each CpG site are summarised in Supplementary file 1G. This table includes the set of protein EpiScores that each CpG contributes to, along with phenotypic annotations (traits) from the MRC-IEU EWAS catalog (MRC-IEU, 2021) for each CpG site having genome-wide significance (p < 3.6 × 10–8) (Saffari et al., 2018). GeneSet enrichment analysis of the original proteins used to train the 109 EpiScores highlighted pathways associated with immune response and cell remodelling, adhesion, and extracellular matrix function (Supplementary file 1H). Figure 2 with 2 supplements see all Download asset Open asset Test performance for the 109 selected protein EpiScores. Test set correlation coefficients for associations between protein EpiScores for (a) inflammatory Olink, (b) neurology Olink, and (c) SOMAmer protein panel EpiScores and measured protein levels are plotted. 95% confidence intervals are shown for each correlation. The 109 protein EpiScores shown had r > 0.1 and p < 0.05 in either one or both of the GS:STRADL (n = 778) and LBC1921 (n = 162) test sets, wherever protein data was available for comparison. Data shown corresponds to the results included in Supplementary file 1B-C. Correlation heatmaps between the 109 EpiScore measures (Figure 2—figure supplement 1) are provided, along with a summary of the most enriched functional pathways for the genes of the 109 proteins used to train EpiScores (Figure 2—figure supplement 2). EpiScore-disease associations in Generation Scotland The Generation Scotland dataset contains extensive electronic health data from GP and hospital records as well as DNAm data for 9537 individuals. This makes it uniquely positioned to test whether EpiScore signals can predict disease onset. We ran nested mixed effects Cox proportional hazards models (Figure 3) to determine whether the levels of each EpiScore at baseline associated with the incidence of 12 morbidities over a maximum of 14 years of follow-up. The correlation structures for the 109 EpiScore measures used for Cox modelling are presented in Figure 2—figure supplement 1. Figure 3 with 1 supplement see all Download asset Open asset Nested Cox proportional hazards assessment of protein EpiScore-disease prediction. Mixed effects Cox proportional hazards analyses in Generation Scotland (n = 9537) tested the relationships between each of the 109 selected EpiScores and the incidence of 12 leading causes of morbidity (Supplementary file 1I-J). The basic model was adjusted for age and sex and yielded 294 associations between EpiScores and disease diagnoses, with false discovery rate (FDR)-adjusted p < 0.05. In the fully adjusted model, which included common risk factors as additional covariates (smoking, deprivation, educational attainment, body mass index (BMI), and alcohol consumption), 137 of the basic model associations remained significant with p < 0.05. In a sensitivity analysis, the addition of estimated white blood cells (WBCs) to the fully adjusted models led to the attenuation of 34 of the 137 associations. In a further sensitivity analysis, 81 associations remained after adjustment for both immune cell proportions and GrimAge acceleration. The Cox proportional hazards assumption was assessed through the Schoenfeld residuals from the models. Two associations in the basic model adjusting for age and sex failed to satisfy the global assumption (across all covariates) and were excluded. There were 294 remaining EpiScore-disease associations with a false discovery rate (FDR)-adjusted p < 0.05 in the basic model. After further adjustment for common risk factor covariates (smoking, social deprivation status, educational attainment, body mass index [BMI], and alcohol consumption), 137 of the 294 EpiScore-disease associations from the basic model had p < 0.05 in the fully adjusted model (Supplementary file 1I-J). Eleven of the 137 fully adjusted associations failed the Cox proportional hazards assumption for the EpiScore variable (p < 0.05 for the association between the Schoenfeld residuals and time; Supplementary file 1K). When we restricted the time-to-event/censor period by each year of possible follow-up, there were minimal differences in the EpiScore-disease hazard ratios between follow-up periods that did not violate the assumption and those that did (Supplementary file 1L). The 137 associations were therefore retained as the primary results. The 137 associations found in the fully adjusted model comprised 78 unique EpiScores that were related to the incidence of 11 of the 12 morbidities studied. Diabetes and chronic obstructive pulmonary disease (COPD) had the greatest number of associations, with 33 and 41, respectively. Figure 4 presents the EpiScore-disease relationships for COPD and the remaining nine morbidities: stroke, lung cancer, ischaemic heart disease (IHD), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), depression, bowel cancer, pain (back/neck), and Alzheimer’s dementia. There were 13 EpiScores that associated with the onset of three or more morbidities. Figure 5 presents relationships for these 13 EpiScores in the fully adjusted Cox model results. Of note is the EpiScore for Complement 5 (C5), which associated with five outcomes: stroke, diabetes, IHD, RA, and COPD. Of the 29 SOMAscan-derived EpiScore associations with incident diabetes, 23 replicated previously reported SOMAscan protein associations (Elhadad et al., 2020; Gudmundsdottir et al., 2020; Ngo et al., 2021) with incident or prevalent diabetes in one or more cohorts (Figure 6 and Supplementary file 1M). Figure 4 Download asset Open asset Protein EpiScore associations with incident disease. EpiScore-disease associations for 10 of the 11 morbidities with associations where p < 0.05 in the fully adjusted mixed effects Cox proportional hazards models in Generation Scotland (n = 9537). Hazard ratios are presented with confidence intervals for 104 of the 137 EpiScore-incident disease associations reported. Models were adjusted for age, sex, and common risk factors (smoking, body mass index (BMI), alcohol consumption, deprivation, and educational attainment). IBD: inflammatory bowel disease. IHD: ischaemic heart disease. COPD: chronic obstructive pulmonary disease. For EpiScore-diabetes associations, see Figure 6. Data shown corresponds to the results included in Supplementary file 1J. Figure 5 Download asset Open asset Protein EpiScores that associated with the greatest number of morbidities. EpiScores with a minimum of three relationships with incident morbidities in the fully adjusted Cox models. The network includes 13 EpiScores as dark blue (SOMAscan) and grey (Olink) nodes, with disease outcomes in black. EpiScore-disease associations with hazard ratios < 1 are shown as blue connections, whereas hazard ratios > 1 are shown in red. COPD: chronic obstructive pulmonary disease. IHD: ischaemic heart disease. Data shown corresponds to the results included in Supplementary file 1J. Figure 6 Download asset Open asset Replication of known protein-diabetes associations with protein EpiScores. EpiScore-incident diabetes associations in Generation Scotland (n = 9537). The 29 SOMAscan (top panel) and four Olink (bottom panel) associations shown with p < 0.05 in fully adjusted mixed effects Cox proportional hazards models. Of the 29 SOMAscan-derived EpiScores, 23 associations were consistent with protein-diabetes associations (pink) in one or more of the comparison studies that used SOMAscan protein levels. Six associations were novel (blue). Data shown corresponds to the results included in Supplementary files 1J and M. Immune cell and GrimAge sensitivity analyses Correlations of the 78 EpiScores that were associated with incident disease (P < 0.05 in the fully-adjusted cox proportional hazards models) with covariates suggested interlinked relationships with both estimated white blood cell proportions and GrimAge acceleration (Figure 3—figure supplement 1). These covariates were therefore added incrementally to the fully-adjusted Cox models (Figure 3). There were 103 associations that remained statistically significant (FDR p < 0.05 in the basic model and p < 0.05 in the fully adjusted model) after adjustment for immune cell proportions, of which 81 remained significant when GrimAge acceleration scores were added to this model (Supplementary file 1J). In a further sensitivity analysis, relationships between both estimated white blood cell (WBC) proportions and GrimAge acceleration scores with incident diseases were assessed in the Cox model structure independently of EpiScores. Of the 60 possible relationships between WBC measures and the morbidities assessed, four were statistically significant (FDR-adjusted p < 0.05) in the basic model and remained significant with p < 0.05 in the fully adjusted model (Supplementary file 1N). A higher proportion of natural killer cells was linked to decreased risk of incident COPD, RA, diabetes, and pain (back/neck). The GrimAge acceleration composite score was associated with COPD, IHD, diabetes, and pain (back/neck) in the fully adjusted models (p < 0.05) (Supplementary file 1O). The magnitude of the GrimAge effect sizes was comparable to the EpiScore findings. Relationship between EpiScores and subsequent COVID-19 Two previous studies including pilot proteomic measurements from the Generation Scotland cohort (N = 199 controls) as part of wider analyses found that several proteins corresponding to our EpiScores were associated with COVID-19 outcomes (Demichev et al., 2021; Messner et al., 2020). These included proteins such as CRP, C9, SELL, and SHBG, all of which were associated with one or more incident diseases in this study. Two subsets (N = 268 and N = 173) of the Generation Scotland sample who contracted COVID-19 were therefore used to test the hypothesis that EpiScores would associate with COVID-19 outcomes (acquired >9 years after the blood draw for DNAm analyses). No significant associations were identified that delineated differences between the development of long-covid (duration >4 weeks) or hospitalisation from COVID-19 (associations that had p < 0.05 did not withstand Bonferroni adjustment for multiple testing) (Supplementary file 1P). Discussion Here, we report a comprehensive DNAm scoring study of 953 circulating proteins. We define 109 robust EpiScores for plasma protein levels that are independent of known pQTL effects. By projecting these EpiScores into a large cohort with extant data linkage, we show that 78 EpiScores associate with the incidence of 11 leading causes of morbidity (137 EpiScore-disease associations in total), but do not associate with COVID-19 outcomes. Finally, we show that EpiScore-diabetes associations highlight previously measured protein-diabetes relationships. The bulk of EpiScore-disease associations are independent of common lifestyle and health factors, differences in immune cell composition and GrimAge acceleration. EpiScores therefore provide methylation-proteomic signatures for disease prediction and risk stratification. The consistency between our EpiScore-diabetes associations and previously identified protein-diabetes relationships (Elhadad et al., 2020; Gudmundsdottir et al., 2020; Ngo et al., 2021) suggests that epigenetic scores identify disease-relevant biological signals. In addition to the comprehensive lookup of SOMAscan proteins with diabetes, several of the markers we identified for COPD and IHD also reflect previous associations with measured proteins (Ganz et al., 2016; Serban et al., 2021). The three studies used for the diabetes comparison represent the largest candidate protein characterisations of type 2 diabetes to date and the top markers identified included aminoacylase-1 (ACY-1), sex hormone-binding globulin (SHBG), growth hormone receptor (GHR), and insulin-like growth factor-binding protein 2 (IFGBP-2) (Elhadad et al., 2020; Gudmundsdottir et al., 2020; Ngo et al., 2021). Our EpiScores for these top markers were also associated with diabetes, in addition to EpiScores for several other protein markers reported in these studies. A growing body of evidence suggests that type 2 diabetes is mediated by genetic and epigenetic regulators (Kwak and Park, 2016) and proteins such as ACY-1 and GHR are thought to influence a range of diabetes-associated metabolic mechanisms (Kim and Park, 2017; Pérez-Pérez et al., 2012). Proteins that we identify through EpiScore associations, such as NTR domain-containing protein 2 (WFIKKN2), have also been causally implicated in type 2 diabetes onset through Mendelian randomisation analysis (Ngo et al., 2021). In the case of diabetes, EpiScores may therefore be used as disease-relevant risk biomarkers, many years prior to onset. Validation should be tested when sufficient data become available for the remaining morbidities. With modest test set performances (e.g., SHBG r = 0.18 and ACY-1 r = 0.25), it is perhaps surprising that such strong synergy is observed between EpiScores for proteins that associated with diabetes and the trends seen with measured proteins. Nonetheless, DNAm scores for CRP and IL-6 have previously been shown to perform modestly in test sets (r ~ 0.2, equivalent to ~4% explained variance in protein level), but augment and often outperform the measured protein related to a range of phenotypes (Stevenson et al., 2020; Stevenson et al., 2021). Compared to scores utilising DNAm for the prediction of singular diseases, our EpiScores enable the granular study of individual protein predictor signatures with clinical outcomes. For example, levels of the acid sphingomyelinase (ASM) EpiScore predicted onset of Alzheimer’s dementia, several years prior to diagnosis. ASM (encoded by SMPD1) has been discussed as a therapeutic candidate for Alzheimer’s disease (Cataldo et al., 2004; Lee et al., 2014; Park et al., 2020) and has been shown to disrupt autophagic protein degradation and associate with accumulation of amyloid-beta in murine models of Alzheimer’s pathology (Lee et al., 2014; Park et al., 2020). Our large-scale assessment of EpiScores provides a platform for future studies, as composite predictors for traits may be created using our EpiScore database. These should be tested in incident disease predictions when sufficient case data are available. Our results indicated that the set of 109 EpiScores are likely to be heavily enriched for inflammatory, complement system and innate immune system pathways, in addition to extracellular matrix, cell remodelling, and cell adhesion pathways. This reinforces previous work linking chronic inflammation and the epigenome (Zaghlool et al., 2020). It also suggests that EpiScores could be useful in the prediction of morbidities that are characterised by differential inflammatory states. An example of this is the EpiScore for Complement Component 5 (C5), which was associated with the onset of five morbidities, the highest number for any EpiScore (Figure 5). The EpiScore for C5 is likely to reflect the biological pathways occurring in individuals with heightened complement cascade activity and could be utilised to alert clinicians to individuals at high risk of multimorbidity. Elevated levels of C5 peptides have been associated with severe inflammatory, autoimmune, and neurodegenerative states (Ma et al., 2019; Mantovani et al., 2014; Morgan and Harris, 2015) and a range of C5-targetting therapeutic approaches are in development (Alawieh et al., 2018; Brandolini et al., 2019; Hawkswo" @default.
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• W4214752021 title "Editor's evaluation: Epigenetic scores for the circulating proteome as tools for disease prediction" @default.
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