Integrated Whole Transcriptome and DNA Methylation Analysis Identifies Gene Networks Specific to Late-Onset Alzheimer's Disease

AbstractBackgroundLate-onset Alzheimer’s disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD represented as variation in DNA methylation (DNAm), we surveyed 420,852 DNAm sites from neurotypical controls (N=49) and late-onset AD patients (N=24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum).ResultsWe identified 858 sites with robust differential methylation, collectively annotated to 772 possible genes (FDR<5%, within 10kb). These sites were overrepresented in AD genetic risk loci (p=0.00655), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR<5%). We analyzed corresponding RNA-seq data to prioritize 130 genes within 10kb of the differentially methylated sites, which were differentially expressed and had expression levels associated with nearby DNAm levels (p<0.05). This validated gene set includes previously reported (e.g. ANK1, DUSP22) and novel genes involved in Alzheimer’s disease, such as ANKRD30B.ConclusionsThese results highlight DNAm changes in Alzheimer’s disease that have gene expression correlates, implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.

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Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles

Genome Medicine ◽

10.1186/s13073-020-00808-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Rosie M. Walker ◽

Kadi Vaher ◽

Mairead L. Bermingham ◽

Stewart W. Morris ◽

Andrew D. Bretherick ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Late Onset ◽

Meta Analysis ◽

Density Lipoprotein ◽

Differentially Methylated Region ◽

Carrier Status ◽

Ε4 Allele ◽

Methylation Patterns

Abstract Background The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised. Methods Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. Results We obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10−100 ≤ P ≤ 2.44 × 10−8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10−4 ≤ P ≤ 3.01 × 10−2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24. Conclusions APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.

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Network propagation of rare mutations in Alzheimer’s disease reveals tissue-specific hub genes and communities

10.1101/781203 ◽

2019 ◽

Author(s):

Marzia A. Scelsi ◽

Valerio Napolioni ◽

Michael D. Greicius ◽

Andre Altmann ◽

◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Networks ◽

Complex Disease ◽

Late Onset ◽

Integrative Approach ◽

Tissue Specific ◽

Association Testing ◽

Wide Range ◽

Network Propagation

ABSTRACTBackgroundState-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein structure and function. Here we present the NETwork Propagation-based Assessment of Genetic Events (NETPAGE), an integrative approach aimed at investigating the biological pathways through which rare variation results in complex disease phenotypes.ResultsWe applied NETPAGE to sporadic, late-onset Alzheimer’s disease (AD), using whole-genome sequencing from the AD Neuroimaging Initiative (ADNI) cohort, as well as whole-exome sequencing from the AD Sequencing Project (ADSP). NETPAGE is based on network propagation, a framework that models information flow on a graph and simulates the percolation of genetic variation through gene networks. The result of network propagation is a set of smoothed gene scores used to predict disease status through sparse regression. The application of NETPAGE to AD enabled the identification of a set of connected genes whose smoothed mutation profile acted as a robust predictor of case-control status, based on gene interactions in the hippocampus. Additionally, smoothed scores significantly correlated with risk of conversion to AD in Mild Cognitive Impairment (MCI) subjects. Lastly, we showed tissue-specific transcriptional dysregulation of the core genes in two independent RNA-seq datasets, as well as significant enrichments in terms and gene sets with known connections to AD.ConclusionsThe presented framework enables enhanced genetic association testing for a wide range of traits, diseases, and sample sizes.

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Genome-wide DNA methylation profiling in nonagenarians suggests an effect of PM20D1 in late onset Alzheimer’s disease

CNS Spectrums ◽

10.1017/s109285292100105x ◽

2021 ◽

pp. 1-27

Author(s):

Carolina Coto-Vílchez ◽

José Jaime Martínez-Magaña ◽

L. Mora-Villalobos ◽

D. Valerio ◽

Alma Delia Genis-Mendoza ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Late Onset ◽

Genome Wide ◽

Dna Methylation Profiling ◽

Methylation Profiling

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P1-053: Genome-wide analysis of DNA methylation differentiates late-onset Alzheimer's disease from dementia with Lewy bodies

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.05.274 ◽

2013 ◽

Vol 9 ◽

pp. P171-P172

Author(s):

Crystal Humphries ◽

Patrice L. Whitehead ◽

Deborah Mash ◽

Gary Beecham ◽

Margaret Pericak-Vance ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Dementia With Lewy Bodies ◽

Late Onset ◽

Lewy Bodies ◽

Genome Wide Analysis ◽

Genome Wide

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Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2

10.1101/815035 ◽

2019 ◽

Author(s):

Rosie M. Walker ◽

Kadi Vaher ◽

Mairead L. Bermingham ◽

Stewart W. Morris ◽

Andrew D. Bretherick ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Late Onset ◽

Meta Analysis ◽

Density Lipoprotein ◽

Differentially Methylated Region ◽

Carrier Status ◽

Ε4 Allele ◽

Methylation Patterns

AbstractBACKGROUNDThe Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, while the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.METHODSUsing the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n=2469) and ε2 (n=1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses.RESULTSWe obtained replicated evidence for DNA methylation differences in a ~169kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 x 10−100≤P≤2.44 x 10−8) and DMRs were identified in SREBF2 and LDLR (1.63 x 10−4≤P≤3.01 x 10−2). Pathway and meQTL analyses implicated lipid-related processes and high density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24.CONCLUSIONSAPOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.

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Alzheimer’s disease-associated (hydroxy)methylomic changes in the brain and blood

Clinical Epigenetics ◽

10.1186/s13148-019-0755-5 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 15

Author(s):

Roy Lardenoije ◽

Janou A. Y. Roubroeks ◽

Ehsan Pishva ◽

Markus Leber ◽

Holger Wagner ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Late Onset ◽

Middle Temporal Gyrus ◽

Promising Target ◽

Subsequent Conversion ◽

Novel Therapeutic Strategies ◽

Genomic Regions ◽

The Brain

Abstract Background Late-onset Alzheimer’s disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (− 3.76% 5mC, pŠidák = 1.07E−06), CHRNB1 (+ 1.46% 5hmC, pŠidák = 4.01E−04), RHBDF2 (− 3.45% UC, pŠidák = 4.85E−06), and C3 (− 1.20% UC, pŠidák = 1.57E−03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, pŠidák = 7.14E−04). Conclusions The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

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