Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease

Silva, Tiago C.; Young, Juan I.; Zhang, Lanyu; Gomez, Lissette; Schmidt, Michael A.; Varma, Achintya; Chen, X. Steven; Martin, Eden R.; Wang, Lily

doi:10.1038/s41467-022-32475-x

Cited by 31 publications

(44 citation statements)

References 112 publications

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“…Nevertheless, the genes identified in our trans-ancestral analyses are biologically plausible. CDH6 has been identified as related to AD in both an epigenome-wide analysis 95 and in an agnostic plasma proteomic analysis. 96 It plays a role in both hippocampal synaptic development and injury.…”

Section: Discussionmentioning

confidence: 99%

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Fongang

Sargurupremraj²,

Jian³

et al. 2022

Preprint

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Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic risk factors and conducted the largest GWAS to date of "all-cause dementia" (ACD) and examined the genetic overlap with VaD. Our dataset includes 809,299 individuals from European, African, Asian, and Hispanic ancestries with 46,902 and 8,702 cases of ACD and VaD, respectively. We replicated known AD loci at genome-wide significance for both ACD and VaD and conducted bioinformatic analyses in prioritizing genes that are functionally relevant and shared with closely related traits and risk factors. For ACD, novel loci were associated with energy transport throughout the brain (SEMA4D), neuronal excitability (ANO3), amyloid plaques deposition in the brain (RBFOX1), and MRI markers of small vessel disease (HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). In addition to the genetic overlap with neurodegenerative processes, genetic risk loci for ACD exhibited overlap with vascular risk factors (Type-II diabetes, blood pressure, lipid levels) and MRI markers of cerebral small vessel disease (cSVD). Our study identified genetic risk loci underlying ACD and VaD that point to the involvement of specific biological pathways and highlights their genetic overlap with vascular risk factors and MRI markers of cSVD. These novel insights could lead to new prevention and treatment strategies.

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Section: Discussionmentioning

confidence: 99%

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Fongang

Sargurupremraj²,

Jian³

et al. 2022

Preprint

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“…Consistent with these previous results, our comparison of the significant blood DNAm from this study with significant brain DNAm associated with AD pathology in two large recent meta-analyses of postmortem brain tissues [ 9 , 110 ] shows only a few overlapping DNAm (3 CpGs and 8 DMRs), mapped to PRSSL1 , LINGO3 , SPRED2 , HOXA2 , NR2F1 , CPT1B , HOXA5 , ZFPM1 genes, and intergenic regions, were significant with both blood DNAm-to-CSF Aβ 42 /pTau 181 association and brain DNAm-to-brain Aβ/tau association (Supplementary Tables 4 – 9 ). Also, there is not any overlap between significant blood DNAm associated with the CSF AD biomarkers and significant blood DNAm associated with clinical AD from our previous meta-analyses of two large clinical AD datasets [ 17 , 111 ]. This is not surprising, given the disconnection between brain pathology and clinical diagnosis in AD; it has been observed that a substantial proportion of cognitively normal subjects also have AD pathology in the brain [ 20 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, given brain and blood cells originate from different developmental cell lineages, previous studies also suggested that DNA methylation profiles are, by and large, distinct between brain and blood [ 7 , 17 , 109 ]. Consistent with these previous results, our comparison of the significant blood DNAm from this study with significant brain DNAm associated with AD pathology in two large recent meta-analyses of postmortem brain tissues [ 9 , 110 ] shows only a few overlapping DNAm (3 CpGs and 8 DMRs), mapped to PRSSL1 , LINGO3 , SPRED2 , HOXA2 , NR2F1 , CPT1B , HOXA5 , ZFPM1 genes, and intergenic regions, were significant with both blood DNAm-to-CSF Aβ 42 /pTau 181 association and brain DNAm-to-brain Aβ/tau association (Supplementary Tables 4 – 9 ).…”

Section: Discussionmentioning

confidence: 99%

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Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects

et al. 2023

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Background Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer’s disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. Methods We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. Results We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau181 in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. Conclusions Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.

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“…Given the modest number of samples with both DNA methylation and CSF biomarker measurements, we expected our analysis to be underpowered. Therefore, based on our experiences and previous studies in the analysis of EWAS measured in blood 37,42,43 , we also prioritized CpGs with suggestive signi cance at the pre-speci ed signi cance threshold P-value < .…”

Section: In Ation Assessment and Correctionmentioning

confidence: 99%

Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects

Zhang

Young

Gomez

et al. 2023

Preprint

Self Cite

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Background Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. Methods We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. Results We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau181 in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. Conclusions Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.

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Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease

Cited by 31 publications

References 112 publications

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects

Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects

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