Abstract
Summary
PhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates ‘phenome scans’, where genetic ...variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner (‘PhenoScanner V2’), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants.
Availability and implementation
PhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk.
PhenoScanner is a curated database of publicly available results from large-scale genetic association studies. This tool aims to facilitate 'phenome scans', the cross-referencing of genetic variants ...with many phenotypes, to help aid understanding of disease pathways and biology. The database currently contains over 350 million association results and over 10 million unique genetic variants, mostly single nucleotide polymorphisms. It is accompanied by a web-based tool that queries the database for associations with user-specified variants, providing results according to the same effect and non-effect alleles for each input variant. The tool provides the option of searching for trait associations with proxies of the input variants, calculated using the European samples from 1000 Genomes and Hapmap.
PhenoScanner is available at www.phenoscanner.medschl.cam.ac.uk CONTACT: jrs95@medschl.cam.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.
In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10
) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for ...nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.
Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke ...outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10
). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.
The fascial system not only enables the body to operate in an integrated manner but modifies its tension in response to the stress on it. Recent animal, cadaveric and in-vitro trials have shown that ...“myofascial force transmission” (MFT) can play a major role in homeostasis, musculoskeletal function and pain. Human evidence for the in-vivo existence of MFT is scarce.
This scoping review attempts to gather and interpret the available evidence of the in-vivo existence of MFT in humans, its role in homeostasis, and musculoskeletal function.
A search of major databases using the keywords 'myofascial force transmission' and 'epimuscular force transmission' yielded 247 articles as of November 2021. For the final analysis, only original in-vivo human studies were considered. In-vitro human studies, cadaveric or animal studies, reviews, and similar studies were excluded. A qualitative analysis of the studies was conducted after rating it with the Oxford's Center for Evidence –based Medicine (CEBM) scale.
Twenty studies ranging from randomized controlled trials (RCTs) to case studies covering 405 patients have been included in this review. The analysed trials were highly heterogeneous and of lower methodological quality meddling with the quantitative analysis. The majority of the appraised studies demonstrated a higher probability of MFT existence, while two studies revealed a lower probability.
Our search for proof of the in vivo existence of MFT in humans has led us to support such an existence, albeit prudently. Previous research on animals and human cadavers reinforces our finding. We are optimistic that the forthcoming studies on the topic will pave the way for the unraveling of several musculoskeletal riddles that are currently unknown or less well-known.
Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol ...to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supports novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homoeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggests that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and serum creatinine. Finally, we demonstrate how a retinol polygenic score could identify individuals more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further investigation with respect to retinol related therapies or nutritional intervention.
Metabolic biomarker data quantified by nuclear magnetic resonance (NMR) spectroscopy in approximately 121,000 UK Biobank participants has recently been released as a community resource, comprising ...absolute concentrations and ratios of 249 circulating metabolites, lipids, and lipoprotein sub-fractions. Here we identify and characterise additional sources of unwanted technical variation influencing individual biomarkers in the data available to download from UK Biobank. These included sample preparation time, shipping plate well, spectrometer batch effects, drift over time within spectrometer, and outlier shipping plates. We developed a procedure for removing this unwanted technical variation, and demonstrate that it increases signal for genetic and epidemiological studies of the NMR metabolic biomarker data in UK Biobank. We subsequently developed an R package, ukbnmr, which we make available to the wider research community to enhance the utility of the UK Biobank NMR metabolic biomarker data and to facilitate rapid analysis.
Physiotherapy has been accepted as an integral part of critical care in developed countries. Preventing and managing pulmonary complications of ventilated and other critically ill patients is still ...considered to be the primary task of physiotherapists in India. As movement experts of the intensive care unit team, physiotherapists play a major role in preventing neuromuscular complications through early mobilization and therapeutic exercise prescription in the developed countries. This critical review analyses the physiological rationale behind the physiotherapeutic technique and existing research evidence pertaining to the role of physiotherapy in critical care. The paper also highlights the simple evidence-based protocol which was successfully implemented in a tertiary care hospital of India.
Post COVID-19 sequelae includes breathlessness, weakness, fatigue, decreased exercise tolerance and impaired quality of life. Physiotherapy based rehabilitation program is an essential component for ...post COVID-19 patients in facilitating maximum functional recovery. Expert consensus statements are available from the developed countries. There is a need for a guidelines to manage post COVID-19 sequelae in Indian context. The objective of this consensus statement is to provide evidence informed guidelines for post COVID-19 physiotherapy management as a component of pulmonary rehabilitation. This consensus statement was developed by expert panel across India. Published literatures were appraised and used to prepare the recommendations. This is the first of its kind of work providing preliminary guidelines for post COVID-19 physiotherapy.
Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel protein biomarkers in AD etiology ...remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets.
We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent.
We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment.
Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.
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