Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer’s disease

Morabito, Samuel; Miyoshi, Emily; Michael, Neethu; Swarup, Vivek

doi:10.1093/hmg/ddaa182

Cited by 54 publications

(52 citation statements)

References 138 publications

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“…Our analyses focused on ALS genetic risk factors, which serve as causal anchors to identify, in an unbiased manner, specific modules that implicate processes involved at the early stages of ALS pathophysiology. Furthermore, immune dysregulation is a common feature in post-mortem tissue from other neurodegenerative and neuropsychiatric disorders 8 , 49 , 50 ; however, the enrichment of genetic risk within upregulated immune genes is complex. For neuropsychiatric disorders such as autism and schizophrenia, the strongest genetic enrichments are within neuronal genes 49 .…”

Section: Discussionmentioning

confidence: 99%

Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

Wang

Ramaswami

Geschwind

2021

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by motor neuron (MN) loss. Multiple genetic risk factors have been identified, implicating RNA and protein metabolism and intracellular transport, among other biological mechanisms. To achieve a systems-level understanding of the mechanisms governing ALS pathophysiology, we built gene co-expression networks using RNA-sequencing data from control human spinal cord samples, identifying 13 gene co-expression modules, each of which represents a distinct biological process or cell type. Analysis of four RNA-seq datasets from a range of ALS disease-associated contexts reveal dysregulation in numerous modules related to ribosomal function, wound response, and leukocyte activation, implicating astrocytes, oligodendrocytes, endothelia, and microglia in ALS pathophysiology. To identify potentially causal processes, we partitioned heritability across the genome, finding that ALS common genetic risk is enriched within two specific modules, SC.M4, representing genes related to RNA processing and gene regulation, and SC.M2, representing genes related to intracellular transport and autophagy and enriched in oligodendrocyte markers. Top hub genes of this latter module include ALS-implicated risk genes such as KPNA3, TMED2, and NCOA4, the latter of which regulates ferritin autophagy, implicating this process in ALS pathophysiology. These unbiased, genome-wide analyses confirm the utility of a systems approach to understanding the causes and drivers of ALS.

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Section: Discussionmentioning

confidence: 99%

Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

Wang

Ramaswami

Geschwind

2021

Sci Rep

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“…Consistent with our findings, these epigenomic studies strongly suggest that non-neuronal cell types contribute to LOAD-specific histone marks associated with active regulatory elements (promoters and enhancers). It was reported that LOAD GWAS loci were enriched in enhancer elements specific to immune cells 57 and tangleassociated H3K9ac signals located in both promoters and enhancers were significantly associated with modules classified as non-neuronal 58 . Recently, two studies used FANS-sorted nuclei followed by ChIP-seq and demonstrated that microglia were the non-neuronal cell type contributing to LOAD epigenomic signatures.…”

Section: Discussionmentioning

confidence: 99%

Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains

Barrera

Song

Safi

et al. 2021

Preprint

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In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer′s disease (LOAD) and translate the associations to causation. Toward that goal, we conducted ATAC-seq profiling using neuronal nuclear protein (NeuN) sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. In conclusion, using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. Furthermore, our results convey mechanistic insights into sex differences in LOAD risk and clinicopathology.

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“…We inquired the publicly available Alzheimer's disease consensus datasets (accessible via: http://swaruplab.bio.uci.edu:3838/bulkRNA/) for IFITM3 expression data 5 (See Supplementary Materials 1 -Expanded Methods for further details).…”

Section: Methodsmentioning

confidence: 99%

“…We also performed confirmatory GSEA on differential gene expression data available from Morabito et al 5 to detect IFITM3 in COVID-19 related datasets and viral infection induced gene signatures. GSEA was performed via the Enrichr platform 7 (Available from: https://maayanlab.cloud/Enrichr/) on the available COVID-19 datasets.…”

Section: Confirmatory Gene Set Enrichment Analyses (Gsea)mentioning

confidence: 99%

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FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology

Vavougios¹,

Breza²,

Nikou³

et al. 2020

Preprint

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Introduction IFITM3, an innate immune protein linked to COVID-19 severity, has recently been identified as a novel γ-secretase modulator. Independent research has shown that IFITM3 may facilitate SARS-CoV-2 neurotropism in an ACE2-independent manner. In a previous study, we had detected perturbations in IFITM3 networks in both the CNS and peripheral immune cells donated by AD patients.The purpose of this study is to explore the transcriptomic evidence of the SARS-CoV-2 / IFITM3 / AD interplay, validating previous findings from our group. Methods Exploratory analyses involved meta-analysis of bulk and single cell RNA data for IFITM3 and FYN differential expression. For confirmatory analyses, we performed gene set enrichment analysis (GSEA) on an AD gene signature from AD Consensus transcriptomics; using the Enrichr platform, we scrutinized COVID-19 datasets for significant, overlapping enriched biological networks. Results Bulk RNA data analysis revealed that IFITM3 and FYN were differentially expressed in two CNS regions in AD: the temporal cortex (AD vs. Controls, adj.p-value=1.3e-6) and the parahippocampal cortex (AD vs. controls, adj.p-value=0.012). Correspondingly, single cell RNA analysis of IFITM3 and FYN revealed that it was differentially expressed in neuronal cells donated from AD patients (astrocytes, microglia and oligodendrocyte precursor cells), when compared to controls. Discussion IFITM3 and by extent FYN were found as interactors within biological networks overlapping between AD and SARS-CoV-2 infection. SARS-CoV-2 SARS-CoV-2-mediated IFITM3 induction would mechanistically result in increased Aβ production. FYN recruitment by viral processes results in abrogation of both fusion of IFITM3 vesicles with lysosomes; immunoevasion, by FYN-mediated impairment of autophagy would then serve to promote impaired detoxification from Aβ, while propagating Tau pathology in an IFITM3-independent manner.

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Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer’s disease

Cited by 54 publications

References 138 publications

Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains

FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology

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