scholarly journals Butyrate and related epigenetic changes link Parkinson's disease to inflammatory bowel disease and depressive symptoms

2021 ◽  
Author(s):  
Aoji Xie ◽  
Elizabeth Ensink ◽  
Peipei Li ◽  
Juozas Gordevicius ◽  
Lee L. Marshall ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Depressive Symptoms ◽  
Gut Microbiome ◽  
Whole Blood ◽  
Blood Samples ◽  
Targeted Bisulfite Sequencing ◽  
Genome Wide ◽  
Whole Blood Samples

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.

scholarly journals Exploratory analysis of age and sex dependent DNA methylation patterns on the X-chromosome in whole blood samples

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Shuxia Li ◽  
Jesper B. Lund ◽  
Kaare Christensen ◽  
Jan Baumbach ◽  
Jonas Mengel-From ◽  
...  
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Whole Blood ◽  
Exploratory Analysis ◽  
Blood Samples ◽  
Whole Blood Samples ◽  
Methylation Patterns ◽  
Age And Sex

scholarly journals Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson’s Disease and exposure to organochlorines reveal glial genes and pathways involved in neurotoxicity

2019 ◽  
Author(s):  
Rodney C.P. Go ◽  
Michael J Corley ◽  
George Webster Ross ◽  
Helen Petrovich ◽  
Kamal H Masaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Epidemiological Studies ◽  
Postmortem Brain ◽  
Genome Wide ◽  
Proinflammatory Responses ◽  
The Central Nervous System ◽  
Pathway Analyses ◽  
Humanmethylation450k Beadchip

Abstract Background: Parkinson’s Disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person’s risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases. Results: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K BeadChip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n=21) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively ( P <0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGC, identified 8 and 18 DML in brain and blood DNA, respectively ( P <0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases. Conclusions : These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

scholarly journals Human-genome gut-microbiome interaction in Parkinson’s disease

2021 ◽  
Author(s):  
Zachary D. Wallen ◽  
William J. Stone ◽  
Stewart A. Factor ◽  
Eric Molho ◽  
Cyrus P. Zabetian ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Human Genome ◽  
Gut Microbiome ◽  
Alpha Synuclein ◽  
Susceptibility Loci ◽  
Opportunistic Pathogens ◽  
Host Genotype ◽  
Genetic Studies ◽  
Genome Wide

AbstractThe causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson’s disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we show that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. This is the first demonstration of interaction between genetic factors in the human genome and the dysbiosis of gut microbiome in PD.

scholarly journals DNA Methylation and Expression Profiles of Whole Blood in Parkinson’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Adrienne R. Henderson ◽  
Qi Wang ◽  
Bessie Meechoovet ◽  
Ashley L. Siniard ◽  
Marcus Naymik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Transcription Factor ◽  
Whole Blood ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Motor Deficits ◽  
Age Related

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease. We performed comparative analyses of the methylome and transcriptome in blood from PD patients and matched controls. Our aim was to characterize DNA methylation and gene expression patterns in whole blood from PD patients as a foundational step toward the future goal of identifying molecular markers that could predict, accurately diagnose, or track the progression of PD. We found that differentially expressed genes (DEGs) were involved in the processes of transcription and mitochondrial function and that PD methylation profiles were readily distinguishable from healthy controls, even in whole-blood DNA samples. Differentially methylated regions (DMRs) were functionally varied, including near transcription factor nuclear transcription factor Y subunit alpha (NFYA), receptor tyrosine kinase DDR1, RING finger ubiquitin ligase (RNF5), acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57 among others. Functional epigenetic modules were highlighted by IL18R1, PTPRC, and ITGB2. We identified patterns of altered disease-specific DNA methylation and associated gene expression in whole blood. Our combined analyses extended what we learned from the DEG or DMR results alone. These studies provide a foundation to support the characterization of larger sample cohorts, with the goal of building a thorough, accurate, and non-invasive molecular PD biomarker.

scholarly journals DNA methylation changes associated with Parkinson’s disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood

Epigenetics ◽  
2019 ◽  
Vol 14 (4) ◽  
pp. 365-382 ◽  
Author(s):  
Adrienne Henderson-Smith ◽  
Kathleen M. Fisch ◽  
Jianping Hua ◽  
Ganqiang Liu ◽  
Eugenia Ricciardelli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Methylation Analysis ◽  
Genome Wide

scholarly journals Exploring human-genome gut-microbiome interaction in Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zachary D. Wallen ◽  
William J. Stone ◽  
Stewart A. Factor ◽  
Eric Molho ◽  
Cyrus P. Zabetian ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gut Microbiome ◽  
Alpha Synuclein ◽  
Incomplete Penetrance ◽  
Susceptibility Loci ◽  
Opportunistic Pathogens ◽  
Host Genotype ◽  
Genome Wide

AbstractThe causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson’s disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we found evidence that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. Results put forth testable hypotheses on the role of gut microbiome in the pathogenesis of PD, the incomplete penetrance of PD susceptibility genes, and potential triggers of pathology in the gut.

scholarly journals Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson’s Disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity

2020 ◽  
Author(s):  
Rodney C.P. Go ◽  
Michael J Corley ◽  
George Webster Ross ◽  
Helen Petrovich ◽  
Kamal H Masaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Epidemiological Studies ◽  
Postmortem Brain ◽  
Genome Wide ◽  
Proinflammatory Responses ◽  
The Central Nervous System ◽  
Pathway Analyses ◽  
Humanmethylation450k Beadchip

Abstract Background: Parkinson’s Disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person’s risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases. Results: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K BeadChip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n=20) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively (P<0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGC, identified 8 and 18 DML in brain and blood DNA, respectively (P <0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases.Conclusions: These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

scholarly journals Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Cancan Qi ◽  
◽  
Judith M. Vonk ◽  
Diana A. van der Plaat ◽  
Maartje A. E. Nieuwenhuis ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Wnt Signaling Pathway ◽  
Persistent Asthma ◽  
Spontaneous Remission ◽  
Chronic Respiratory Disease ◽  
Normal Lung ◽  
Blood Samples ◽  
Cpg Sites ◽  
Whole Blood Samples

Abstract Background Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. Methods Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA). Results We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P < 0.05) and the same direction of effect in nasal brushes. Conclusion We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway.

scholarly journals Parkinson’s Disease-Associated, Sex-specific Changes in DNA Methylation at PARK7 (DJ-1), ATXN1, SLC17A6, NR4A2, and PTPRN2 in Cortical Neurons

2021 ◽  
Author(s):  
Joseph Kochmanski ◽  
Nathan C. Kuhn ◽  
Alison I. Bernstein
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Cortical Neurons ◽  
Disease Risk ◽  
Neuronal Population ◽  
Tissue Samples ◽  
Genome Wide ◽  
Dna Modifications ◽  
The Relationship

AbstractEvidence for epigenetic regulation playing a role in Parkinson’s disease (PD) is growing, particularly for DNA modifications. Approximately 90% of PD cases are due to a complex interaction between age, genes, and environmental factors, and epigenetic marks are thought to mediate the relationship between aging, genetics, the environment, and disease risk. To date, there are a small number of published genome-wide studies of DNA modifications in PD, but none accounted for cell-type or sex in their analyses. Given the hetereogeneity of bulk brain tissue samples and known sex differences in PD risk, progression, and severity, these are critical variables to account for. In this first genome-wide analysis of DNA methylation in an enriched neuronal population from PD post-mortem parietal cortex, we report sex-specific PD-associated methylation changes in PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), NR4A2 (NURR1), and other genes involved in developmental pathways, neurotransmitter packaging and release, and axon and neuron projection guidance.

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