Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Shi, Liu; Buchanan, Colin R; Cox, Simon R.; Hillary, Robert F.; Marioni, Riccardo E.; Campbell, Archie; Hayward, Caroline; Stolicyn, Aleks; Whalley, Heather C.; Harris, Mathew A.; Waymont, Jennifer M.J.; Waiter, Gordon D.; Backhouse, Ellen V.; Wardlaw, Joanna M.; Steele, J. Douglas; McIntosh, Andrew M.; Lovestone, Simon; Buckley, Noel J.; Nevado‐Holgado, Alejo J.

doi:10.1002/dad2.12240

Cited by 6 publications

(3 citation statements)

References 69 publications

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“…No studies have performed SOMAmer-based, whole proteome PheWAS studies of the brain imaging and cognitive score traits we have profiled in a heathy ageing population that were not enriched for neurodegenerative diseases. However, replication of associations from several studies 9 , 29 , 30 was found for a small subset of associations (Supplementary Data 19 ).…”

Section: Resultsmentioning

confidence: 72%

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

et al. 2022

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Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.

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Section: Resultsmentioning

confidence: 72%

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

et al. 2022

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“…No studies have performed SOMAmer-based, whole proteome PheWAS studies of the brain imaging and cognitive score traits we have profiled in a heathy ageing population that were not enriched for neurodegenerative diseases. However, replication of associations from several studies 9, 29, 30 was found for a small subset of associations (Supplementary Table 19).…”

Section: Resultsmentioning

confidence: 73%

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

Gadd

Hillary

McCartney

et al. 2021

Preprint

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Characterising associations between the epigenome, proteome and phenome may provide insight into molecular regulation of biological pathways governing health. However, epigenetic signatures for many neurologically-associated plasma protein markers remain uncharacterised. Here, we report an epigenome and phenome-wide association study of the circulating proteome in relation to brain health. We perform epigenome-wide studies of 4,235 plasma proteins (n=778), identifying 2,895 CpG-protein associations (protein quantitative trait methylation loci; pQTMs) after stringent correction for multiple testing. These were independent of known genetic protein quantitative trait loci (pQTL) and common lifestyle effects, extending current knowledge by analysing a further 3,286 protein measurements with 2,854 novel pQTMs. We then perform a phenome-wide study of each protein in relation to neurological traits in 1,065 individuals, identifying 644 proteins related to cognitive, brain imaging phenotypes or APOE status. By integrating our pQTM dataset with our phenome association study, we uncovered 88 epigenetic associations for protein markers of neurological traits, 83 of which were previously unreported. These data are pertinent to understanding heterogeneity in brain health.

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“…For both cohorts, WMH scores were derived for each participant using the Fazekas and Wahlund visual scales (Fazekas et al, 1987;Wahlund et al, 2001) by a trained observer (EB, ZM, checked by JMW) blind to clinical and all other information. Using the Fazekas scale, WMH were defined as punctuate, focal or diffuse lesions in the deep or periventricular white matter, basal ganglia or brainstem, where they appeared as visible areas of hyperintensity on the FLAIR images (Shi et al, 2021). Severity of WMH was graded as 0 (absent) to 3 (severe) for periventricular and deep WMH.…”

Section: White Matter Hyperintensity Phenotypesmentioning

confidence: 99%

‘Inflammaging’ in Major Depressive Disorder: Associations between markers of inflammation and brain ageing in depression across two large community-based cohorts

Green

Squillace

Stevenson

et al. 2021

Preprint

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BackgroundMajor Depressive Disorder (MDD) is associated with accelerated ageing trajectories including functional markers of ageing, cellular ageing and markers of poor brain health. The biological mechanisms underlying these associations remain poorly understood. Chronic inflammation is also associated with advanced ageing; however, the degree to which long-term inflammation plays a role in ageing in MDD remains unclear, partly due to difficulties differentiating long-term inflammation from acute cross-sectional measures.MethodsHere, we use a longer-term measure of inflammation: a DNA methylation-based marker of C-reactive protein (DNAm CRP), in a large cohort of individuals deeply phenotyped for MDD (Generation Scotland, GS; N=804). We investigate associations between DNAm CRP and serum CRP using linear modelling with two brain ageing neuroimaging-derived phenotypes: (i) a machine learning based measure of brain-predicted age difference (brain-PAD) and (ii) white matter hyperintensities (WMH). We then examine inflammation by depression interaction effects for these brain ageing phenotypes. We sought to replicate findings in an independent sample of older community-dwelling adults (Lothian Birth Cohort 1936, LBC1936; N=615).ResultsDNAm CRP was significantly associated with increased brain-PAD (β=0.111, p=0.015), which was replicated in the independent sample with a similar significant effect size (β=0.114, p=0.012). There were no associations between the inflammation markers and WMH phenotypes in the GS-imaging sample, however in the LBC1936 sample, DNAm CRP was significantly associated with both Wahlund infratentorial (β=0.15, PFDR= 0.006) and Fazekas deep white matter hyperintensity scores (β= 0.116, PFDR=0.033). There were no interaction effects between inflammation and MDD in either cohort.ConclusionsThis study found robust associations between a longer-term marker of inflammation and brain ageing as measured by brain-PAD, consistent across two large independent samples. However, we found no evidence for interaction effects between inflammation and MDD on any brain ageing phenotype in these community-based cohorts. These findings provide evidence that chronic inflammation is associated with increased brain ageing, which is not specific to MDD. Future work should investigate these relationships in clinical samples including with other inflammatory biomarkers and should furthermore aim to determine causal directionality.

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Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Cited by 6 publications

References 69 publications

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

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

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

‘Inflammaging’ in Major Depressive Disorder: Associations between markers of inflammation and brain ageing in depression across two large community-based cohorts

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