Systematic analysis to identify transcriptome-wide dysregulation of Alzheimer’s disease in genes and isoforms

Fan, Cong; Chen, Ken; Zhou, Jiaxin; Wong, Ping-Pui; He, Dan; Huang, Yiqi; Wang, Xin; Ling, Tianze; Yang, Yuedong; Zhao, Huiying

doi:10.1007/s00439-020-02230-7

Cited by 15 publications

(9 citation statements)

References 88 publications

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“…Michael J. Ganda et al estimated the candidate risk genes of three psychiatric disorders based on GWAS summary statistics and isoform-level expression profiles. They emphasized the importance of isoform-level gene regulatory mechanisms in defining cell type and disease specificity 18 , and similar analyses and conclusions were generated for Alzheimer’s disease 19 .…”

Section: Introductionmentioning

confidence: 72%

“…CC-BY 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted June 9, 2021. ; https://doi.org/10.1101/2021.06.08.447608 doi: bioRxiv preprint of isoform-level gene regulatory mechanisms in defining cell type and disease specificity , and similar analyses and conclusions were generated for Alzheimer's disease 19 .…”

Section: Introductionmentioning

confidence: 91%

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MCGA: a multi-strategy conditional gene-based association framework integrating with isoform-level expression profiles reveals new susceptible and druggable candidate genes of schizophrenia

Jiang

Xue

et al. 2021

Preprint

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Linkage disequilibrium and disease-associated variants in non-coding regions make it difficult to distinguish truly associated genes from redundantly associated genes for complex diseases. In this study, we proposed a new conditional gene-based framework called MCGA that leveraged an improved effective chi-squared statistic to control the type I error rates and remove the redundant associations. MCGA initially integrated two conventional strategies to map genetic variants to genes, i.e., mapping a variant to its physically nearby gene and mapping a variant to a gene if the variant is a gene-level expression quantitative trait locus (eQTL) of the gene. We further performed a simulation study and demonstrated that the isoform-level eQTL was more powerful than the gene-level eQTL in the association analysis. Then the third strategy, i.e., mapping a variant to a gene if the variant is an isoform-level eQTL of the gene, was also integrated with MCGA. We applied MCGA to predict the potential susceptibility genes of schizophrenia and found that the potential susceptibility genes identified by MCGA were enriched with many neuronal or synaptic signaling-related terms in the Gene Ontology knowledgebase and antipsychotics-gene interaction terms in the drug-gene interaction database (DGIdb). More importantly, nine susceptibility genes were the target genes of multiple approved antipsychotics in DrugBank. Comparing the susceptibility genes identified by the above three strategies implied that strategy based on isoform-level eQTL could be an important supplement for the other two strategies and help predict more candidate susceptibility isoforms and genes for complex diseases in a multi-tissue context.

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Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 91%

MCGA: a multi-strategy conditional gene-based association framework integrating with isoform-level expression profiles reveals new susceptible and druggable candidate genes of schizophrenia

Jiang

Xue

et al. 2021

Preprint

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show abstract

“…Michael Gandal et al estimated the candidate risk genes of three psychiatric disorders based on GWAS summary statistics and isoform-level expression profiles. They emphasized the importance of isoform-level gene regulatory mechanisms in defining cell type and disease specificity ( Gandal et al, 2018 ), and similar analyses and conclusions were generated for Alzheimer’s disease ( Fan et al, 2021 ).…”

Section: Introductionmentioning

confidence: 83%

A conditional gene-based association framework integrating isoform-level eQTL data reveals new susceptibility genes for schizophrenia

Jiang

Xue

et al. 2022

eLife

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Linkage disequilibrium and disease-associated variants in the non-coding regions make it difficult to distinguish the truly associated genes from the redundantly associated genes for complex diseases. In this study, we proposed a new conditional gene-based framework called eDESE that leveraged an improved effective chi-squared statistic to control the type I error rates and remove the redundant associations. eDESE initially performed the association analysis by mapping variants to genes according to their physical distance. We further demonstrated that the isoform-level eQTLs could be more powerful than the gene-level eQTLs in the association analysis using a simulation study. Then the eQTL-guided strategies, that is, mapping variants to genes according to their gene/isoform-level variant-gene cis-eQTLs associations, were also integrated with eDESE. We then applied eDESE to predict the potential susceptibility genes of schizophrenia and found that the potential susceptibility genes were enriched with many neuronal or synaptic signaling-related terms in the Gene Ontology knowledgebase and antipsychotics-gene interaction terms in the drug-gene interaction database (DGIdb). More importantly, seven potential susceptibility genes identified by eDESE were the target genes of multiple antipsychotics in DrugBank. Comparing the potential susceptibility genes identified by eDESE and other benchmark approaches (i.e., MAGMA and S-PrediXcan) implied that strategy based on the isoform-level eQTLs could be an important supplement for the other two strategies (physical distance and gene-level eQTLs). We have implemented eDESE in our integrative platform KGGSEE (http://pmglab.top/kggsee/#/) and hope that eDESE can facilitate the prediction of candidate susceptibility genes and isoforms for complex diseases in a multi-tissue context.

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“…The amyloid precursor protein (APP) serves as the key polypeptide originator from which all amyloid-beta (Aβ) peptide variants are finally derived from upon sequential proteolytic processing via β-site APP cleaving enzyme (BACE) and γ-secretases [ 152 , 153 , 154 ]. A detailed elaboration of the etiopathogenesis of AD has been given in various excellent reviews [ 155 , 156 , 157 , 158 , 159 , 160 ] and will not be further addressed here. Instead, this review focuses on the modulation of APP/Aβ processing in the context of a proamyloidogenic environment.…”

Section: Gabaergic Neurotransmission and App/aβ Processing In Alzheim...mentioning

confidence: 99%

Cav3 T-Type Voltage-Gated Ca2+ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on Pharmacotherapy and Pharmacovigilance

Papazoglou

Arshaad

Henseler

et al. 2022

IJMS

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Voltage-gated Ca2+ channels (VGCCs) were reported to play a crucial role in neurotransmitter release, dendritic resonance phenomena and integration, and the regulation of gene expression. In the septohippocampal system, high- and low-voltage-activated (HVA, LVA) Ca2+ channels were shown to be involved in theta genesis, learning, and memory processes. In particular, HVA Cav2.3 R-type and LVA Cav3 T-type Ca2+ channels are expressed in the medial septum-diagonal band of Broca (MS-DBB), hippocampal interneurons, and pyramidal cells, and ablation of both channels was proven to severely modulate theta activity. Importantly, Cav3 Ca2+ channels contribute to rebound burst firing in septal interneurons. Consequently, functional impairment of T-type Ca2+ channels, e.g., in null mutant mouse models, caused tonic disinhibition of the septohippocampal pathway and subsequent enhancement of hippocampal theta activity. In addition, impairment of GABA A/B receptor transcription, trafficking, and membrane translocation was observed within the septohippocampal system. Given the recent findings that amyloid precursor protein (APP) forms complexes with GABA B receptors (GBRs), it is hypothesized that T-type Ca2+ current reduction, decrease in GABA receptors, and APP destabilization generate complex functional interdependence that can constitute a sophisticated proamyloidogenic environment, which could be of potential relevance in the etiopathogenesis of Alzheimer’s disease (AD). The age-related downregulation of T-type Ca2+ channels in humans goes together with increased Aβ levels that could further inhibit T-type channels and aggravate the proamyloidogenic environment. The mechanistic model presented here sheds new light on recent reports about the potential risks of T-type Ca2+ channel blockers (CCBs) in dementia, as observed upon antiepileptic drug application in the elderly.

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Systematic analysis to identify transcriptome-wide dysregulation of Alzheimer’s disease in genes and isoforms

Cited by 15 publications

References 88 publications

MCGA: a multi-strategy conditional gene-based association framework integrating with isoform-level expression profiles reveals new susceptible and druggable candidate genes of schizophrenia

MCGA: a multi-strategy conditional gene-based association framework integrating with isoform-level expression profiles reveals new susceptible and druggable candidate genes of schizophrenia

A conditional gene-based association framework integrating isoform-level eQTL data reveals new susceptibility genes for schizophrenia

Cav3 T-Type Voltage-Gated Ca2+ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on Pharmacotherapy and Pharmacovigilance

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