ArticlePLoS genetics2012
Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 77 citations in OpenAlex.
- Comorbidity Genes of Alzheimer's Disease and Type 2 Diabetes Associated with Memory and Cognitive Function.International journal of molecular sciences · 2024Review
- The Deficits of Insulin Signal in Alzheimer's Disease and the Mechanisms of Vanadium Compounds in Curing AD.Current issues in molecular biology · 2023Review
- Predictive network analysis identifies JMJD6 and other potential key drivers in Alzheimer's disease.Communications biology · 2023Article
- Amyloid β-Peptide Effects on Glucose Regulation Are Dependent on Apolipoprotein E Genotype.eNeuro · 2023Article
- Mouse Models with SGLT2 Mutations: Toward Understanding the Role of SGLT2 beyond Glucose Reabsorption.International journal of molecular sciences · 2023Review
- Analysis of a genetic region affecting mouse body weight.Physiological genomics · 2023Article
- The role of peripheral β-amyloid in insulin resistance, insulin secretion, and prediabetes:Frontiers in endocrinology · 2023Article
- Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR.Metabolites · 2022Article
- Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation.Genome research · 2022Article
- PharmOmics: A species- and tissue-specific drug signature database and gene-network-based drug repositioning tool.iScience · 2022Article
- Peripheral Aβ acts as a negative modulator of insulin secretion.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Mergeomics 2.0: a web server for multi-omics data integration to elucidate disease networks and predict therapeutics.Nucleic acids research · 2021Article
- Alternative exon splicing and differential expression in pancreatic islets reveals candidate genes and pathways implicated in early diabetes development.Mammalian genome : official journal of the International Mammalian Genome Society · 2021Article
- Article
- Gene networks and pathways for plasma lipid traits via multitissue multiomics systems analysis.Journal of lipid research · 2021Article
- Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood.Neurobiology of aging · 2021Article
- Mouse Systems Genetics as a Prelude to Precision Medicine.Trends in genetics : TIG · 2020Review
- HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats.Diabetes · 2020Article
- Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues.American journal of physiology. Endocrinology and metabolism · 2019Article
- Integrative Genomics Analysis Unravels Tissue-Specific Pathways, Networks, and Key Regulators of Blood Pressure Regulation.Frontiers in cardiovascular medicine · 2019Article
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 1 country.
Funding
Abstract
Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptin(ob/ob) mutation (Lep(ob)). High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.
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