Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Gadd, Danni A; Hillary, Robert F.; McCartney, Daniel L.; Shi, Liu; Stolicyn, Aleks; Robertson, Neil; Martin, Richard M; McGeachan, Robert I; Campbell, Archie; Shen, Xueyi; Barbu, Miruna C.; Green, Claire; Morris, Stewart W.; Harris, Mathew A.; Backhouse, Ellen V.; Steele, J. Douglas; Oyarzún, Diego A.; Muñiz‐Terrera, Graciela; Ritchie, Craig W.; Nevado‐Holgado, Alejo J.; Chandra, Tamir; Hayward, Caroline; Evans, Kathryn; Porteous, David J.; Cox, Simon R.; Whalley, Heather C.; McIntosh, Andrew M.; Marioni, Riccardo E.

doi:10.1038/s41467-022-32319-8

Cited by 23 publications

(19 citation statements)

References 95 publications

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“…A previous study demonstrated wide-spread association between protein abundance and DNAm 30 . We conducted a proteome-wide association analysis study (PWAS) for MD-MS seeking to reveal the potentially downstream proteomic consequences of the measured DNAm differences.…”

Section: Association Between Md-ms and Inflammatory Protein Markersmentioning

confidence: 93%

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

Shen,

Barbu,

Caramaschi

et al. 2023

Preprint

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Major Depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation (DNAm) may be associated with the condition. However, previous DNAm studies have not so far been widely replicated, suggesting a need for larger meta-analysis studies. In the present study, the Psychiatric Genomics Consortium Major Depressive Disorder working group conducted a meta-analysis of methylome-wide association analysis (MWAS) for life-time MD across 18 studies of 24,754 European-ancestry participants (5,443 MD cases) and an East Asian sample (243 cases, 1846 controls). We identified fifteen CpG sites associated with lifetime MD with methylome-wide significance (p < 6.42×10-8). Top CpG effect sizes in European ancestries were positively correlated with those from an independent East Asian MWAS (r = 0.482 and p = 0.068 for significant CpG sites, r = 0.261 and p = 0.009 for the top 100 CpG sites). Methylation score (MS) created using the MWAS summary statistics was significantly associated with MD status in an out-of-sample classification analysis (β = 0.122, p = 0.005, AUC = 0.53). MS was also associated with five inflammatory markers, with the strongest association found with Tumor Necrosis Factor Beta (β=-0.154, p=1.5×10-5). Mendelian randomisation (MR) analysis demonstrated that 23 CpG sites were potentially causally associated with MD and six of those were replicated in an independent mQTL dataset (Wald’s ratio test, absolute β ranged from 0.056 to 0.932, p ranged from 7×10-3to 4.58×10-6). CpG sites located in the Major Histocompatibility complex (MHC) region showed the strongest evidence from MR analysis of being associated with MD. Our study provides evidence that variations in DNA methylation are associated with MD, and further evidence supporting involvement of the immune system. Larger sample sizes in diverse ancestries are likely to reveal replicable associations to improve mechanistic inferences with the potential to inform molecular target identification.

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Section: Association Between Md-ms and Inflammatory Protein Markersmentioning

confidence: 93%

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

Shen,

Barbu,

Caramaschi

et al. 2023

Preprint

Self Cite

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“…These adjustments are imperfect, as they do not include every immune cell and rare subpopulations therefore likely exist that are unaccounted for. For example, two MWAS of blood protein levels reported associations between pappasylin (PAPPA) and various DNAm sites; however, after adjustment for eosinophil proportions, these signals were attenuated [100,101]. An expanded cell-type deconvolution panel for 56 immune cell profiles has recently become available and may aid in the separation of extrinsic and intrinsic signals [102].…”

Section: Cell Type Proportions In Mpsmentioning

confidence: 99%

An overview of DNA methylation-derived trait score methods and applications

et al. 2023

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Microarray technology has been used to measure genome-wide DNA methylation in thousands of individuals. These studies typically test the associations between individual DNA methylation sites (“probes”) and complex traits or diseases. The results can be used to generate methylation profile scores (MPS) to predict outcomes in independent data sets. Although there are many parallels between MPS and polygenic (risk) scores (PGS), there are key differences. Here, we review motivations, methods, and applications of DNA methylation-based trait prediction, with a focus on common diseases. We contrast MPS with PGS, highlighting where assumptions made in genetic modeling may not hold in epigenetic data.

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“…However, ITIH4 levels were reduced (Kim et al 2019 ). The results of GWAS analysis found that ITIH3/ITIH1 genes were directly related to brain health; higher levels would cause more damage to the brain tissue (Gadd et al 2022 ). Proprotein convertase subtilisin/kexin type 9 (PCSK9) has shown interaction with high-density lipoproteins in coronary artery disease, and interestingly, crosslinking mass spectrometry analysis identifies the interaction of PCSK9 with ITIH1 (hyaluronan binder) and apoA1 in immunoHDL (Burnap et al 2021 ).…”

Section: Roles Of Liver Secretomementioning

confidence: 99%

Non-alcoholic fatty liver disease and liver secretome

2022

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Metabolism of carbohydrates and lipids and protein degradation occurs in the liver and contributes to the body's homeostasis by secreting a variety of mediators. Any imbalance in this homeostasis due to excess fat consumption and the pathologic events accompanying lipotoxicity, autophagy dysregulation, endoplasmic reticulum stress, and insulin resistance may cause disturbances in the secretion of the proteins from the liver and their physiologic modifications and interactions with others. Since the liver secretome plays a role in the regulation of fuel metabolism and inflammation not only in the liver per se but also in other organs, the proteins belong to the utmost targets for treating metabolic and inflammatory diseases (e.g., COVID-19), depending on the available and feasible approaches to controlling their biological effects. However, in this era, we still come across new liver-derived proteins but are yet unable to entirely understand the pathologic basis underlying disease progression. This review aims to provide an updated overview of liver secretome biology with explanatory mechanisms with regard to the progression of metabolic and inflammatory liver diseases.

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Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Cited by 23 publications

References 95 publications

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

An overview of DNA methylation-derived trait score methods and applications

Non-alcoholic fatty liver disease and liver secretome

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