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Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease.

ABSTRACT: We developed an endophenotype disease module-based methodology for Alzheimer's disease (AD) drug repurposing and identified sildenafil as a potential disease risk modifier. Based on retrospective case-control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25-0.39, P<1.0×10^-8). Propensity score stratified analyses confirmed that sildenafil is significantly associated with a decreased risk of AD across all four drug cohorts we tested (diltiazem, glimepiride, losartan and metformin) after adjusting age, sex, race, and disease comorbidities. We also found that sildenafil increases neurite growth and decreases phospho-tau expression in AD patient-induced pluripotent stem cells-derived neuron models, supporting mechanistically its potential beneficial effect in Alzheimer's disease. The association between sildenafil use and decreased incidence of AD does not establish causality or its direction, which requires a randomized clinical trial approach.

SUBMITTER: Fang J

PROVIDER: S-EPMC9097949 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease.

Fang Jiansong J Zhang Pengyue P Zhou Yadi Y Chiang Chien-Wei CW Tan Juan J Hou Yuan Y Stauffer Shaun S Li Lang L Pieper Andrew A AA Cummings Jeffrey J Cheng Feixiong F

Nature aging 20211206 12

We developed an endophenotype disease module-based methodology for Alzheimer's disease (AD) drug repurposing and identified sildenafil as a potential disease risk modifier. Based on retrospective case-control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25-0.39, P<1.0×10<sup>-8</sup>). Propensity score stratified analys ...[more]

PMID: 35572351

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Project description:Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

Project description:BACKGROUND: In silico candidate gene prioritisation (CGP) aids the discovery of gene functions by ranking genes according to an objective relevance score. While several CGP methods have been described for identifying human disease genes, corresponding methods for prokaryotic gene function discovery are lacking. Here we present two prokaryotic CGP methods, based on phylogenetic profiles, to assist with this task. RESULTS: Using gene occurrence patterns in sample genomes, we developed two CGP methods (statistical and inductive CGP) to assist with the discovery of bacterial gene functions. Statistical CGP exploits the differences in gene frequency against phenotypic groups, while inductive CGP applies supervised machine learning to identify gene occurrence pattern across genomes. Three rediscovery experiments were designed to evaluate the CGP frameworks. The first experiment attempted to rediscover peptidoglycan genes with 417 published genome sequences. Both CGP methods achieved best areas under receiver operating characteristic curve (AUC) of 0.911 in Escherichia coli K-12 (EC-K12) and 0.978 Streptococcus agalactiae 2603 (SA-2603) genomes, with an average improvement in precision of >3.2-fold and a maximum of >27-fold using statistical CGP. A median AUC of >0.95 could still be achieved with as few as 10 genome examples in each group of genome examples in the rediscovery of the peptidoglycan metabolism genes. In the second experiment, a maximum of 109-fold improvement in precision was achieved in the rediscovery of anaerobic fermentation genes in EC-K12. The last experiment attempted to rediscover genes from 31 metabolic pathways in SA-2603, where 14 pathways achieved AUC >0.9 and 28 pathways achieved AUC >0.8 with the best inductive CGP algorithms. CONCLUSION: Our results demonstrate that the two CGP methods can assist with the study of functionally uncategorised genomic regions and discovery of bacterial gene-function relationships. Our rediscovery experiments also provide a set of standard tasks against which future methods may be compared.

Dataset Information

Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease.

Publications

Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease.

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