A Comprehensive Analysis Identified Hub Genes and Associated Drugs in Alzheimer’s Disease

Jing, Qi; Zhang, Hui; Sun, Xiaoru; Xu, Yaru; Cao, Silu; Fang, Yiling; Zhao, Xuan; Li, Cheng

doi:10.1155/2021/8893553

Cited by 12 publications

(8 citation statements)

References 41 publications

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“…In particular, Avg-valid+SR identified a total of 89 significant TWAS risk genes of AD dementia with p-values < 2.5 × 10 :9 . Of these, 19 are known GWAS risk genes, 70 are within 1Mb of a known GWAS risk gene, and 14 have been previously observed as TWAS risk genes of AD dementia [19][20][21][22][23][24] (Supplementary Table 4).…”

Section: Twas Results Of Ad Dementiamentioning

confidence: 99%

SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning

Parrish

Buchman

Tasaki

et al. 2023

Preprint

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Multiple reference panels of a given tissue or multiple tissues often exist, and multiple regression methods could be used for training gene expression imputation models for TWAS. To leverage expression imputation models (i.e., base models) trained with multiple reference panels, regression methods, and tissues, we develop a Stacked Regression based TWAS (SR-TWAS) tool which can obtain optimal linear combinations of base models for a given validation transcriptomic dataset. Both simulation and real studies showed that SR-TWAS improved power due to increased effective training sample sizes and borrowed strength across multiple regression methods and tissues. Leveraging base models across multiple reference panels, tissues, and regression methods, our studies of Alzheimer's disease (AD) dementia and Parkinson's disease (PD) identified respective 11 independent significant risk genes for AD (supplementary motor area tissue) and 12 independent significant risk genes for PD (substantia nigra tissue), including 6 novels for AD and 6 novels for PD.

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Section: Twas Results Of Ad Dementiamentioning

confidence: 99%

SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning

Parrish

Buchman

Tasaki

et al. 2023

Preprint

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“…Gene based rare variant analysis of RFX7 in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort showed trending significance with entorhinal cortex thickness 76 . ITGB4, the index gene at the Aβ40TBS locus, encodes a transmembrane integrin involved in cell-to-cell adhesion, is differentially expressed in AD [77][78][79][80] with potential roles in the blood-brain barrier 81,82 , schizophrenia and bipolar disorder 83 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins

Oatman

Reddy

Quicksall

et al. 2022

Preprint

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Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Main protein components of these hallmarks include Aβ40, Aβ42, tau, phospho-tau and APOE. With the exception of the APOE-ϵ4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

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“…5e). Interestingly, APLNR and SLC14A1 have also been found to be upregulated in AD [43][44][45][46] . The function of KIF1A has been shown to be impaired in the presence of Aβ oligomers 47 .…”

Section: Discussionmentioning

confidence: 99%

Spatially Resolved Transcriptomics Reveals Gene Signatures Underlying the Vulnerability of Human Middle Temporal Gyrus in Alzheimer's Disease

Chen

Chang

et al. 2021

SSRN Journal

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Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer's disease (AD); however, little is known about the molecular mechanisms underlying this regional vulnerability. Here we use the 10x Visium platform to de ne the spatial topography of gene expression in the MTG from both early AD and control cases. We identify differentially expressed genes (DEGs) and enriched pathways that may contribute to the layer-speci c vulnerability of AD pathology. Also, gene co-expression analyses reveal four gene modules, which signi cantly change their co-expression patterns in the presence of variations of AD pathology. Furthermore, we validate the changes of key representative DEGs that are associated with AD pathology using single-molecule uorescent in situ hybridization. In summary, we provide a rich resource for the spatial transcriptomic pro le of the human MTG, which will contribute to our understanding of the complex architecture and AD pathology of this vulnerable brain region.

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A Comprehensive Analysis Identified Hub Genes and Associated Drugs in Alzheimer’s Disease

Cited by 12 publications

References 41 publications

SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning

SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins

Spatially Resolved Transcriptomics Reveals Gene Signatures Underlying the Vulnerability of Human Middle Temporal Gyrus in Alzheimer's Disease

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