scholarly journals Sex-specific DNA methylation changes in Alzheimer’s disease pathology

2021 ◽  
Author(s):  
Lanyu Zhang ◽  
Juan Young ◽  
Lissette Gomez ◽  
Tiago Silva ◽  
Michael Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Association Studies ◽  
Specific Treatment ◽  
Type I ◽  
Braak Stage ◽  
Biological Processes ◽  
Specific Manner

Abstract Sex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation changes in AD, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with AD in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated AD genes, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation changes were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Importantly, a number of drugs commonly prescribed for AD patients also targeted these genes with sex-specific DNA methylation changes. Our study implicated multiple new loci and biological processes that affected AD in a sex-specific manner and highlighted the importance of sex-specific treatment regimens for AD patients.

scholarly journals Sex-specific DNA methylation changes in Alzheimer’s disease pathology

2021 ◽  
Author(s):  
Lanyu Zhang ◽  
Juan I. Young ◽  
Lissette Gomez ◽  
Tiago C. Silva ◽  
Michael A. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Association Studies ◽  
Specific Treatment ◽  
Type I ◽  
Braak Stage ◽  
Biological Processes ◽  
Specific Manner

AbstractSex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation changes in AD, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with AD in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated AD genes, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation changes were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Importantly, a number of drugs commonly prescribed for AD patients also targeted these genes with sex-specific DNA methylation changes. Our study implicated multiple new loci and biological processes that affected AD in a sex-specific manner and highlighted the importance of sex-specific treatment regimens for AD patients.

scholarly journals Sex-specific DNA methylation differences in Alzheimer’s disease pathology

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Lanyu Zhang ◽  
Juan I. Young ◽  
Lissette Gomez ◽  
Tiago C. Silva ◽  
Michael A. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Interaction Analysis ◽  
Epigenetic Modification ◽  
Association Studies ◽  
Type I ◽  
Braak Stage ◽  
Biological Processes ◽  
Specific Manner

AbstractSex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation differences in AD neuropathology, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort, we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with the AD Braak stage in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated genes in AD neuropathology, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation differences were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Our study implicated multiple new loci and biological processes that affected AD neuropathology in a sex-specific manner.

scholarly journals A gene-level methylome-wide association analysis identifies novel Alzheimer’s disease genes

2020 ◽  
Author(s):  
Chong Wu ◽  
Jonathan Bradley ◽  
Yanming Li ◽  
Lang Wu ◽  
Hong-Wen Deng
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Association Studies ◽  
Error Rates ◽  
Supplementary Information ◽  
Type I ◽  
Wide Range ◽  
Gene Level

AbstractMotivationTranscriptome-wide association studies (TWAS) have successfully facilitated the discovery of novel genetic risk loci for many complex traits, including late-onset Alzheimer’s disease (AD). However, most existing TWAS methods rely only on gene expression and ignore epigenetic modification (i.e., DNA methylation) and functional regulatory information (i.e., enhancer-promoter interactions), both of which contribute significantly to the genetic basis of AD.ResultsThis motivates us to develop a novel gene-level association testing method that integrates genetically regulated DNA methylation and enhancer-target gene pairs with genome-wide association study (GWAS) summary results. Through simulations, we show that our approach, referred to as the CMO (cross methylome omnibus) test, yielded well controlled type I error rates and achieved much higher statistical power than competing methods under a wide range of scenarios. Furthermore, compared with TWAS, CMO identified an average of 124% more associations when analyzing several brain imaging-related GWAS results. By analyzing to date the largest AD GWAS of 71,880 cases and 383,378 controls, CMO identified six novel loci for AD, which have been ignored by competing methods.Availability and implementationSoftware: https://github.com/ChongWuLab/[email protected] informationSupplementary data are available at Bioinformatics online.

scholarly journals A gene-level methylome-wide association analysis identifies novel Alzheimer’s disease genes

2021 ◽  
Author(s):  
Chong Wu ◽  
Jonathan Bradley ◽  
Yanming Li ◽  
Lang Wu ◽  
Hong-Wen Deng
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Association Studies ◽  
Error Rates ◽  
Supplementary Information ◽  
Type I ◽  
Wide Range ◽  
Gene Level

Abstract Motivation Transcriptome-wide association studies (TWAS) have successfully facilitated the discovery of novel genetic risk loci for many complex traits, including late-onset Alzheimer’s disease (AD). However, most existing TWAS methods rely only on gene expression and ignore epigenetic modification (i.e., DNA methylation) and functional regulatory information (i.e., enhancer-promoter interactions), both of which contribute significantly to the genetic basis of AD. Results We develop a novel gene-level association testing method that integrates genetically regulated DNA methylation and enhancer-target gene pairs with genome-wide association study (GWAS) summary results. Through simulations, we show that our approach, referred to as the CMO (cross methylome omnibus) test, yielded well controlled type I error rates and achieved much higher statistical power than competing methods under a wide range of scenarios. Furthermore, compared with TWAS, CMO identified an average of 124% more associations when analyzing several brain imaging-related GWAS results. By analyzing to date the largest AD GWAS of 71,880 cases and 383,378 controls, CMO identified six novel loci for AD, which have been ignored by competing methods. Availability Software: https://github.com/ChongWuLab/CMO Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Lanyu Zhang ◽  
Tiago C. Silva ◽  
Juan I. Young ◽  
Lissette Gomez ◽  
Michael A. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Prefrontal Cortex ◽  
Biomarker Discovery ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Braak Stage ◽  
Polycomb Repressive Complex 2 ◽  
Differentially Methylated Genes

AbstractDNA methylation differences in Alzheimer’s disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. Using a uniform analysis pipeline, we identified 3751 CpGs and 119 differentially methylated regions (DMRs) significantly associated with Braak stage. Our analysis identified differentially methylated genes such as MAMSTR, AGAP2, and AZU1. The most significant DMR identified is located on the MAMSTR gene, which encodes a cofactor that stimulates MEF2C. Notably, MEF2C cooperates with another transcription factor, PU.1, a central hub in the AD gene network. Our enrichment analysis highlighted the potential roles of the immune system and polycomb repressive complex 2 in pathological AD. These results may help facilitate future mechanistic and biomarker discovery studies in AD.

scholarly journals Epidemiological pathology of Aβ deposition in the ageing brain in CFAS: addition of multiple Aβ-derived measures does not improve dementia assessment using logistic regression and machine learning approaches

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
S. B. Wharton ◽  
◽  
D. Wang ◽  
C. Parikh ◽  
F. E. Matthews ◽  
...  
Keyword(s):  
Machine Learning ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Logistic Regression ◽  
Neuritic Plaque ◽  
Type I ◽  
Ageing Population ◽  
Braak Stage ◽  
Age Related ◽  
Highly Correlated

AbstractAβ-amyloid deposition is a key feature of Alzheimer’s disease, but Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessment, based on neuritic plaque density, shows a limited relationships to dementia. Thal phase is based on a neuroanatomical hierarchy of Aβ-deposition, and in combination with Braak neurofibrillary tangle staging also allows derivation of primary age-related tauopathy (PART). We sought to determine whether Thal Aβ phase predicts dementia better than CERAD in a population-representative cohort (n = 186) derived from the Cognitive Function and Ageing Study (CFAS). Cerebral amyloid angiopathy (CAA) was quantitied as the number of neuroanatomical areas involved and cases meeting criteria for PART were defined to determine if they are a distinct pathological group within the ageing population. Agreement with the Thal scheme was excellent. In univariate analysis Thal phase performed less well as a predictor of dementia than CERAD, Braak or CAA. Logistic regression, decision tree and linear discriminant analysis were performed for multivariable analysis, with similar results. Thal phase did not provide a better explanation of dementia than CERAD, and there was no additional benefit to including more than one assessment of Aβ in the model. Number of areas involved by CAA was highly correlated with assessment based on a severity score (p < 0.001). The presence of capillary involvement (CAA type I) was associated with higher Thal phase and Braak stage (p < 0.001). CAA was not associated with microinfarcts (p = 0.1). Cases satisfying pathological criteria for PART were present at a frequency of 10.2% but were not older and did not have a higher likelihood of dementia than a comparison group of individuals with similar Braak stage but with more Aβ. They also did not have higher hippocampal-tau stage, although PART was weakly associated with increased presence of thorn-shaped astrocytes (p = 0.048), suggesting common age-related mechanisms. Thal phase is highly applicable in a population-representative setting and allows definition of pathological subgroups, such as PART. Thal phase, plaque density, and extent and type of CAA measure different aspects of Aβ pathology, but addition of more than one Aβ measure does not improve dementia prediction, probably because these variables are highly correlated. Machine learning predictions reveal the importance of combining neuropathological measurements for the assessment of dementia.

Alzheimer's disease genetics: lessons to improve disease modelling

2011 ◽  
Vol 39 (4) ◽  
pp. 910-916 ◽  
Author(s):  
Rita J. Guerreiro ◽  
John Hardy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Biological Processes ◽  
Complete Understanding ◽  
Genome Wide ◽  
History Of ◽  
Ad Alzheimer’S Disease

In the present review, we look back at the recent history of GWAS (genome-wide association studies) in AD (Alzheimer's disease) and integrate the major findings with current knowledge of biological processes and pathways. These topics are essential for the development of animal models, which will be fundamental to our complete understanding of AD.

scholarly journals Meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex

2020 ◽  
Author(s):  
Rebecca G. Smith ◽  
Ehsan Pishva ◽  
Gemma Shireby ◽  
Adam R. Smith ◽  
Janou A.Y. Roubroeks ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Meta Analysis ◽  
Brain Regions ◽  
Braak Stage ◽  
Combine Data ◽  
Online Data ◽  
Data Resource ◽  
Significance Threshold

ABSTRACTEpigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identified 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identified 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes had not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a > 600 further unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

scholarly journals DNA Methylation: A Promising Approach in Management of Alzheimer’s Disease and Other Neurodegenerative Disorders

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 90
Author(s):  
Gagandeep Kaur ◽  
Suraj Singh S. Rathod ◽  
Mohammed M. Ghoneim ◽  
Sultan Alshehri ◽  
Javed Ahmad ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Neurodegenerative Diseases ◽  
Epigenetic Modification ◽  
Research Area ◽  
Potential Biomarker ◽  
Novel Biomarkers ◽  
Different Populations

DNA methylation, in the mammalian genome, is an epigenetic modification that involves the transfer of a methyl group on the C5 position of cytosine to derive 5-methylcytosine. The role of DNA methylation in the development of the nervous system and the progression of neurodegenerative diseases such as Alzheimer’s disease has been an interesting research area. Furthermore, mutations altering DNA methylation affect neurodevelopmental functions and may cause the progression of several neurodegenerative diseases. Epigenetic modifications in neurodegenerative diseases are widely studied in different populations to uncover the plausible mechanisms contributing to the development and progression of the disease and detect novel biomarkers for early prognosis and future pharmacotherapeutic targets. In this manuscript, we summarize the association of DNA methylation with the pathogenesis of the most common neurodegenerative diseases, such as, Alzheimer’s disease, Parkinson’s disease, Huntington diseases, and amyotrophic lateral sclerosis, and discuss the potential of DNA methylation as a potential biomarker and therapeutic tool for neurogenerative diseases.

scholarly journals Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Makoto Hashimoto ◽  
Gilbert Ho ◽  
Shuei Sugama ◽  
Takato Takenouchi ◽  
Masaaki Waragai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transforming Growth Factor ◽  
Association Studies ◽  
Meta Analysis ◽  
Amyloid Β ◽  
Activin A ◽  
Antagonistic Pleiotropy ◽  
Type I ◽  
Genome Wide Association Studies

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer’s disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ 42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

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