scholarly journals Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases

2022 ◽  
Author(s):  
Huiling Zhao ◽  
humaira Rasheed ◽  
Therese Haugdahl Nost ◽  
Yoonsu Cho ◽  
Yi Liu ◽  
...  
Keyword(s):  
Drug Targets ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Drug Repurposing ◽  
Population Data ◽  
Limited Data ◽  
Specific Effects ◽  
Clinical Trial Evidence ◽  
Males And Females ◽  
Trial Evidence

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans, but limited data has made identification of causal proteins in other ancestries challenging. Here we present a multi-ancestry proteome-wide MR analysis pipeline based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the causal effects of 1,545 proteins on eight complex diseases in up to 32,658 individuals of African ancestries and 1.22 million individuals of European ancestries. We identified 45 and seven protein-disease pairs with MR and genetic colocalization evidence in the two ancestries respectively. 15 protein-disease pairs showed evidence of differential effects between males and females. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence of an effect in both ancestries, seven pairs with European-specific effects and seven with African-specific effects. Integrating these MR signals with observational and clinical trial evidence, we were able to evaluate the efficacy of one existing drug, identify seven drug repurposing opportunities and predict seven novel effects of proteins on diseases. Our results highlight the value of proteome-wide MR in informing the generalisability of drug targets across ancestries and illustrate the value of multi-cohort and biobank meta-analysis of genetic data for drug development.

scholarly journals Updated Review and Meta-Analysis of Probiotics for the Treatment of Clinical Depression: Adjunctive vs. Stand-Alone Treatment

2021 ◽  
Vol 10 (4) ◽  
pp. 647
Author(s):  
Viktoriya L. Nikolova ◽  
Anthony J. Cleare ◽  
Allan H. Young ◽  
James M. Stone
Keyword(s):  
Meta Analysis ◽  
Clinical Depression ◽  
Controlled Clinical Trial ◽  
Reactive Protein ◽  
Treatment Type ◽  
Antidepressant Effects ◽  
Clinical Trial Evidence ◽  
Randomised Controlled ◽  
Trial Evidence ◽  
Insight Into

Recent years have seen a rapid increase in the use of gut microbiota-targeting interventions, such as probiotics, for the treatment of psychiatric disorders. The objective of this update review was to evaluate all randomised controlled clinical trial evidence on the efficacy of probiotics for clinical depression. Cochrane guidelines for updated reviews were followed. By searching PubMed and Web of Science databases, we identified 546 new records since our previous review. A total of seven studies met selection criteria, capturing 404 people with depression. A random effects meta-analysis using treatment type (stand-alone vs. adjunctive) as subgroup was performed. The results demonstrated that probiotics are effective in reducing depressive symptoms when administered in addition to antidepressants (SMD = 0.83, 95%CI 0.49–1.17), however, they do not seem to offer significant benefits when used as stand-alone treatment (SMD = −0.02, 95%CI −0.34–0.30). Potential mechanisms of action may be via increases in brain-derived neurotrophic factor (BDNF) and decreases in C-reactive protein (CRP), although limited evidence is available at present. This review offers stronger evidence to support the clinical use of probiotics in depressed populations and provides an insight into the mode of administration more likely to yield antidepressant effects.

scholarly journals Genomics-driven drug discovery based on disease-susceptibility genes

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Kyuto Sonehara ◽  
Yukinori Okada
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Disease Susceptibility ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Drug Repurposing ◽  
Susceptibility Genes ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Disease Associations

AbstractGenome-wide association studies have identified numerous disease-susceptibility genes. As knowledge of gene–disease associations accumulates, it is becoming increasingly important to translate this knowledge into clinical practice. This challenge involves finding effective drug targets and estimating their potential side effects, which often results in failure of promising clinical trials. Here, we review recent advances and future perspectives in genetics-led drug discovery, with a focus on drug repurposing, Mendelian randomization, and the use of multifaceted omics data.

scholarly journals Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257784
Author(s):  
Rajaneesh K. Gupta ◽  
Enyinna L. Nwachuku ◽  
Benjamin E. Zusman ◽  
Ruchira M. Jha ◽  
Ava M. Puccio
Keyword(s):  
Gene Networks ◽  
Drug Targets ◽  
Drug Repositioning ◽  
Meta Analysis ◽  
Drug Repurposing ◽  
Gene Signature ◽  
Airway Epithelial Cells ◽  
Gene Ranking ◽  
Human Airway ◽  
Ranking Algorithms

Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic—COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature’-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.

scholarly journals Genome-wide meta-analysis of pneumonia suggests a role for mucin biology and provides novel drug repurposing opportunities

2021 ◽  
Author(s):  
William R. Reay ◽  
Michael P. Geaghan ◽  
Murray J. Cairns ◽  
Keyword(s):  
Drug Targets ◽  
Meta Analysis ◽  
Low Frequency ◽  
Drug Repurposing ◽  
The Elderly ◽  
Risk Scores ◽  
Polygenic Effect ◽  
Genome Wide ◽  
A Genome ◽  
Mucin Genes

ABSTRACTPneumonia remains one of the leading causes of death worldwide, particularly amongst the elderly and young children. We performed a genome-wide meta-analysis of lifetime pneumonia diagnosis (N=266,277), that encompassed the largest collection of cases published to date. Genome-wide significant associations with pneumonia were uncovered for the first time beyond the major histocompatibility complex region, with three novel loci, including a signal fine-mapped to a cluster of mucin genes. Moreover, we demonstrated evidence of a polygenic effect of common and low frequency pneumonia associated variation impacting several other mucin genes and O-glycosylation, further suggesting a role for these processes in pneumonia pathophysiology. The pneumonia GWAS was then leveraged to identify drug repurposing opportunities, including evidence that supports the use of lipid modifying agents in the prevention and treatment of the disorder. We also propose how polygenic risk could be utilised for precision drug repurposing through pneumonia risk scores constructed using variants mapped to pathways with known drug targets. In summary, we provide novel insights into the genetic architecture of pneumonia susceptibility, with future study warranted to functionally interrogate novel association signals and evaluate the suitability of the compounds prioritised by this study as repositioning candidates.

scholarly journals Age-specific effects of body size on fracture risk in later life: A lifecourse Mendelian randomization study

2021 ◽  
Author(s):  
Grace M. Power ◽  
Jon H. Tobias ◽  
Timothy M. Frayling ◽  
Jess Tyrrell ◽  
April Hartley ◽  
...  
Keyword(s):  
Body Size ◽  
Fracture Risk ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Later Life ◽  
Observational Research ◽  
Mineral Density ◽  
Specific Effects ◽  
Inverse Variance ◽  
Using Data

AbstractMusculoskeletal conditions, including fractures, can have severe and long-lasting consequences. Higher body mass index in adulthood is widely acknowledged to be protective for most fracture sites, indicated through previous clinical and epidemiological observational research. However, the association between weight and bone health is complex and sources of bias, induced by confounding factors, may have distorted earlier findings. Employing a lifecourse Mendelian randomization (MR) approach by using genetic instruments to separate effects at different life stages, this investigation aims to explore how prepubertal and adult body size independently influence fracture risk in later life.Using data from a large UK-based prospective cohort, univariable and multivariable MR with inverse variance weighted meta-analysis were conducted to simultaneously estimate the effects of age-specific genetic proxies for body size (n=453,169) on the odds of fracture in later life (n=416,795). A two-step MR framework was additionally applied to elucidate potential mediators. Univariable and multivariable MR indicated strong evidence that higher body size in childhood reduced fracture risk in later life (OR, 95% CI: 0.89, 0.82 to 0.96, P=0.005 and OR, 95% CI: 0.76, 0.69 to 0.85, P=1×10−6, respectively). Conversely, higher body size in adulthood increased fracture risk (OR, 95% CI: 1.08, 1.01 to 1.16, P=0.023 and OR, 95% CI: 1.26, 1.14 to 1.38, P=2×10−6, respectively). Two-step MR analyses suggested that the effect of higher body size in childhood on reduced fracture risk was mediated by its influence on higher estimated bone mineral density (eBMD) in adulthood.This investigation provides novel evidence that higher body size in childhood has a direct effect on reduced fracture risk in later life through its influence on increased eBMD. Results indicate that higher body size in adulthood is a risk factor for fractures, opposing findings from earlier research. Protective effect estimates previously observed are likely attributed to childhood effects.

scholarly journals Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Catherine S. Storm ◽  
Demis A. Kia ◽  
Mona M. Almramhi ◽  
Sara Bandres-Ciga ◽  
Chris Finan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Target Identification ◽  
Causal Effect ◽  
Age At Onset ◽  
Drug Repurposing

AbstractParkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.

scholarly journals Drug Repurposing of potential drug targets for treatment of COVID-19

2021 ◽  
Author(s):  
Rajaneesh Gupta ◽  
Enyinna Nwachuku ◽  
Benjamin Zusman ◽  
Ruchira Jha ◽  
Ava Puccio
Keyword(s):  
Gene Networks ◽  
Drug Targets ◽  
Drug Repositioning ◽  
Meta Analysis ◽  
Drug Repurposing ◽  
Gene Signature ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Gene Ranking ◽  
Ranking Algorithms

Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic-COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature'-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.

scholarly journals Effectiveness of Pharmacopuncture for Asthma: A Systematic Review and Meta-Analysis

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Feng-Yan Shen ◽  
Myeong Soo Lee ◽  
Sung-Ki Jung
Keyword(s):  
Systematic Review ◽  
Randomized Clinical Trials ◽  
Data Extraction ◽  
Meta Analysis ◽  
Inclusion Criteria ◽  
Clinical Trial Evidence ◽  
Potential Benefits ◽  
Herbal Therapies ◽  
Trial Evidence ◽  
Selection Of

Pharmacopuncture is a new needle therapy that integrates acupuncture and herbal therapies, and it has the potential to treat many diseases. A systematic review was performed to summarize and critically evaluate clinical trial evidence regarding the effectiveness of pharmacopuncture for asthma. Eight electronic databases and six journals were searched in this study. Randomized clinical trials (RCTs) in which human patients with asthma were treated with pharmacopuncture were included. The selection of studies, data extraction, and validation were performed independently by two reviewers. Four RCTs met our inclusion criteria, and the evidence from all RCTs in this study was positive. The meta-analysis showed statistically significant effects of pharmacopuncture compared to conventional treatment (n=341,Risk Ratio=1.13, 95% CI of 1.05 to 1.23,P=.002, heterogeneity:χ2=3.55,P=.31,I2=16%). Two trials showed favorable effects of pharmacopuncture on peak expiratory flow (PEF). However, few rigorous trials have tested the effects of pharmacopuncture on asthma. The results of our systematic review point to the potential benefits of pharmacopuncture for adults with asthma, and we suggest further RCTs and the development of a standard method of pharmacopuncture therapy.

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