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Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ad_mci]

ABSTRACT: Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ad_mci]

PROVIDER: PRJNA591098 | ENA |

REPOSITORIES: ENA

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Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ftd]

Project description:The role of peripheral inflammation in dementia is an important but complex topic. We present here the largest cohort of peripheral blood gene expression data ever assembled from patients with dementia and matching controls. Importantly, this cohort includes individuals from a diverse set of dementia disorders, including Alzheimer’s Disease (AD), mild cognitive impairment (MCI), and multiple disorders within the frontotemporal dementia (FTD) spectrum. We found strong transcriptional evidence of an innate immune inflammatory response, mediated by monocytes and neutrophils, in AD, MCI, and two FTD subtypes, PSP and nfvPPA. This transcriptional inflammatory response is enriched for genetic risk for AD, in part because it is also enriched for microglial genes, which have previously been implicated in AD risk. Finally, we show that this transcriptional response is strongly enriched for binding of the transcription factors PU.1 and RELA, which have previously been linked to AD risk and progression.

2020-11-13 | GSE140830 | GEO

Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ad_mci]

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Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders

Project description:Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders

| PRJNA591096 | ENA

Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ftd]

Project description:Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ftd]

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Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-11-13 | GSE140831 | GEO

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Project description:People with neurodegenerative disorders have diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) is a widely studied chemical modification to DNA, and increasing evidence suggests that DNAm alterations play an important role in neurodegenerative disorders. In this study we aimed to identify shared blood DNAm differences between 471-1,522 controls and people with Alzheimer’s disease (N = 161), amyotrophic lateral sclerosis (N = 3,032) and Parkinson’s disease (N = 1,132). We used a mixed-linear model method (MOMENT) that has been shown to account for the effect of (un)known confounders, to test for association of each DNAm site with each disorder. A fixed-effects meta-analysis of Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease results identified 12 differentially methylated positions passing a genome-wide significant threshold. Predicted immune cell-type proportions were disrupted across all neurodegenerative disorders, as well as schizophrenia and rheumatoid arthritis. Protein inflammatory markers were correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy ageing cohort. In contrast, they were not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. We have identified shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

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Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

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DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopment disorders

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DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopment disorders [RNA-Seq]

Project description:Mutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here we define the effects of neurodevelopmental disease-associated DNMT3A mutations. We show that diverse mutations affect different aspects of protein activity yet lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.

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