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

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Dec. 20, 2021

Parkinson'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 investigate over 3,000 genes encode druggable proteins predict their efficacy as targets for disease. expression protein quantitative trait loci mimic exposure medications, we examine the causal effect on risk (in two large cohorts), age at onset progression. propose 23 drug-targeting mechanisms disease, including four possible repurposing opportunities drugs which may increase risk. Of these, put forward six with strongest evidence. There remarkably little overlap between our reduce versus progression, suggesting different molecular mechanisms. Drugs genetic support are considerably more likely succeed clinical trials, provide compelling evidence an analysis pipeline prioritise development.

Language: Английский

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Proteomic profiling platforms head to head: Leveraging genetics and clinical traits to compare aptamer- and antibody-based methods

Science Advances, Journal Year: 2022, Volume and Issue: 8(33)

Published: Aug. 19, 2022

High-throughput proteomic profiling using antibody or aptamer-based affinity reagents is used increasingly in human studies. However, direct analyses to address the relative strengths and weaknesses of these platforms are lacking. We assessed findings from SomaScan1.3K ( N = 1301 reagents), SomaScan5K platform 4979 Olink Explore 1472 reagents) techniques 568 adults Jackson Heart Study 219 participants HERITAGE Family across four performance domains: precision, accuracy, analytic breadth, phenotypic associations leveraging detailed clinical phenotyping genetic data. Across studies, we show evidence supporting more reliable protein target specificity a higher number for platform, while Soma benefit greater measurement precision breadth proteome.

Language: Английский

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Shared mechanisms across the major psychiatric and neurodegenerative diseases

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 26, 2022

Several common psychiatric and neurodegenerative diseases share epidemiologic risk; however, whether they pathophysiology is unclear the focus of our investigation. Using 25 GWAS results LD score regression, we find eight significant genetic correlations between diseases. We integrate with human brain transcriptomes (n = 888) proteomes 722) to identify cis- trans- transcripts proteins that are consistent a pleiotropic or causal role in each disease, referred as for brevity. Within disease group, many distinct shared proteins. Remarkably, 30% (13 42) disorders. Furthermore, 2.6-fold more protein-protein interactions among than expected by chance. Together, findings suggest these have molecular pathophysiology, which has important ramifications early treatment therapeutic development.

Language: Английский

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Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

PLoS Medicine, Journal Year: 2021, Volume and Issue: 18(6), P. e1003605 - e1003605

Published: June 1, 2021

Background Increased vitamin D levels, as reflected by 25-hydroxy (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, levels are associated with many confounding variables, thus associations described date may not be causal. Vitamin Mendelian randomization (MR) studies provided results that concordant large-scale randomized trials. Here, we used 2-sample MR assess evidence supporting a causal effect of circulating 25OHD susceptibility severity. Methods findings Genetic variants strongly genome-wide association study (GWAS) 443,734 participants European ancestry (including 401,460 from the UK Biobank) were instrumental variables. GWASs susceptibility, hospitalization, severe disease Host Genetics Initiative outcome GWASs. These included up 14,134 individuals COVID-19, 1,284,876 without 11 countries. SARS-CoV-2 positivity was determined laboratory testing or medical chart review. Population controls also control groups for all outcomes, including hospitalization disease. Analyses restricted descent when possible. Using inverse-weighted MR, genetically increased 1 standard deviation logarithmic scale had no significant (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p 0.44), (OR 1.09; CI: 0.89, 1.33; 0.41), 0.97; 0.77, 1.22; 0.77). We an additional 6 meta-analytic methods, well conducting sensitivity analyses after removal at risk horizontal pleiotropy, obtained similar results. limited weak instrument bias some analyses. Further, our do apply deficiency. Conclusions In this study, did observe support between severity, hospitalization. Hence, supplementation means protecting worsened outcomes is supported genetic evidence. Other therapeutic preventative avenues should given higher priority controlled

Language: Английский

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Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

BMC Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Jan. 11, 2022

Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due bias. In order examine altered genetically predicted concentration of circulating cytokines associated with development, we performed a two-sample Mendelian randomisation (MR) analysis.

Language: Английский

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