A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

eLife, Journal Year: 2020, Volume and Issue: 9

Published: July 7, 2020

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular that provides therapeutic intervention points can be addressed with existing FDA-approved pharmaceuticals. The entry point virus is ACE2, which component of counteracting hypotensive axis RAS. Bradykinin potent part vasopressor system induces hypotension and vasodilation degraded by ACE enhanced angiotensin1-9 produced ACE2. perform new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) patients were used to sequence virus. Comparison BALF controls identifies critical imbalance RAS represented decreased combination increases renin, angiotensin, key receptors, kinogen many kallikrein enzymes activate it, both bradykinin receptors. This very atypical pattern predicted elevate levels multiple tissues systems will likely cause vascular dilation, permeability hypotension. These bradykinin-driven outcomes explain symptoms being observed COVID-19.In late 2019, named SARS-CoV-2, causes humans called COVID-19, emerged China quickly spread around world. Many individuals infected develop only mild, including cough, high temperature loss sense smell; while others may no at all. However, some much more severe, life-threatening affecting lungs other parts body heart brain. SARS-CoV-2 uses human enzyme ACE2 like ‘Trojan Horse’ sneak into its host. lowers blood pressure works against another known as (which has opposite effect). Therefore, balance maintain normal pressure. It remains unclear whether affects how work. When first emerged, team researchers studied collected help them identify Garvin et al. analyzed previous work investigate changes regulates contribute COVID-19. analyses found caused lung decrease, increased. turn increased molecule (referred ‘Bradykinin Storm’). . Previous studies have shown pain vessels expand become leaky lead swelling inflammation surrounding tissue. In addition, production substance hyaluronic acid was could degrade it greatly decreased. Hyaluronic absorb than 1,000 times own weight water form hydrogel. Bradykinin-Storm-induced leakage combined excess would result Jello-like preventing oxygen uptake carbon dioxide release severely affected patients. findings suggest Storm responsible severe Further experiments identified several medicinal drugs potential re-purposed treat Storm. A possible next step carry out clinical trials assess effective these treating understanding SARS-Cov-2 clinicians who most risk developing symptoms.

Language: Английский

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Stroke genetics informs drug discovery and risk prediction across ancestries

Nature, Journal Year: 2022, Volume and Issue: 611(7934), P. 115 - 123

Published: Sept. 30, 2022

Previous genome-wide association studies (GWASs) of stroke - the second leading cause death worldwide were conducted predominantly in populations European ancestry1,2. Here, cross-ancestry GWAS meta-analyses 110,182 patients who have had a (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify signals for its subtypes at 89 (61 new) independent loci: 60 primary inverse-variance-weighted analyses 29 secondary meta-regression multitrait analyses. On basis internal validation an follow-up 89,084 additional cases (30% 1,013,843 87% risk loci 60% replicated (P < 0.05). Effect sizes highly correlated across ancestries. Cross-ancestry fine-mapping, silico mutagenesis analysis3, transcriptome-wide proteome-wide revealed putative causal genes (such as SH3PXD2A FURIN) variants GRK5 NOS3). Using three-pronged approach4, provide genetic evidence drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 VCAM1 possible targets, with drugs already under investigation F11 PROC. A polygenic score integrating ancestry-specific GWASs vascular-risk factor (integrative scores) strongly predicted ischaemic European, East Asian African ancestry5. Stroke scores predictive clinical factors 52,600 clinical-trial participants cardiometabolic disease. Our results insights to inform biology, reveal potential targets derive prediction tools

Language: Английский

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Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer’s and Parkinson’s diseases

Nature Genetics, Journal Year: 2020, Volume and Issue: 52(11), P. 1158 - 1168

Published: Oct. 26, 2020

Language: Английский

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A large-scale genome-wide association study meta-analysis of cannabis use disorder

The Lancet Psychiatry, Journal Year: 2020, Volume and Issue: 7(12), P. 1032 - 1045

Published: Oct. 20, 2020

BackgroundVariation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) is associated with negative outcomes, including increased risk of psychopathology. The aim the study was conduct large genome-wide association (GWAS) identify novel variants disorder.MethodsTo this GWAS meta-analysis associations loci, we used samples from Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, deCODE (20 916 case samples, 363 116 control total), contrasting cases controls. To examine overlap between 22 traits interest (chosen because previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised chronotype] disorder), linkage disequilibrium score regression calculate correlations.FindingsWe identified two significant loci: chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) 8 (near CHRNA2 EPHX2, SNP rs4732724; OR 0·89, 0·86–0·93, p=6·46 10−9). Cannabis were genetically correlated (rg 0·50, p=1·50 10−21), but they showed significantly different 12 tested, suggesting at least partially underpinnings disorder. positively other psychopathology, ADHD, major depression, schizophrenia.InterpretationThese findings support theory that shared there distinction disorder.FundingNational Institute Mental Health; National on Alcohol Abuse Alcoholism; Drug Abuse; Center for Personalized Medicine Centre Integrative Sequencing; European Commission, Horizon 2020; Child Health Human Development; Research Council New Zealand; Aging; Wellcome Trust Case Control Consortium; UK Innovation Medical (UKRI MRC); Brain & Behavior Foundation; Deafness Other Communication Disorders; Services Administration (SAMHSA); Biomedical Imaging Bioengineering; (NHMRC) Australia; Tobacco-Related Disease Program University California; Families Borderline Personality Disorder (Beth Rob Elliott) 2018 NARSAD Young Investigator Grant; Foundation (Cure Kids); Canterbury Zealand Lottery Grants Board; Otago; Carney Pharmacogenomics; James Hume Bequest Fund; Institutes Health: Genes, Environment Initiative; Cancer Institute; William T Grant Australian Council; Virginia Tobacco Settlement VISN 1 4 Illness Research, Education, Clinical Centers US Department Veterans Affairs; 5th Framework Programme (FP-5) GenomEUtwin Project; Lundbeck NIH-funded Shared Instrumentation S10RR025141; Translational Sciences Award grants; Neurological Stroke; Heart, Lung, Blood General Sciences.

Language: Английский

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Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(10), P. 1367 - 1376

Published: Aug. 26, 2021

Language: Английский

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A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(9), P. 1284 - 1292

Published: June 2, 2022

Language: Английский

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Natural Variation in Crops: Realized Understanding, Continuing Promise

Annual Review of Plant Biology, Journal Year: 2021, Volume and Issue: 72(1), P. 357 - 385

Published: Jan. 22, 2021

Crops feed the world's population and shape human civilization. The improvement of crop productivity has been ongoing for almost 10,000 years evolved from an experience-based to a knowledge-driven practice over past three decades. Natural alleles their reshuffling are long-standing genetic changes that affect how crops respond various environmental conditions agricultural practices. Decoding basis natural variation is central understanding evolution and, in turn, improving breeding. Here, we review current advances approaches used map causal variation, provide refined insights into genetics outline this knowledge promises drive development sustainable agriculture under dome emerging technologies.

Language: Английский

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Role of the Gut-Brain Axis in the Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders

JAMA Psychiatry, Journal Year: 2023, Volume and Issue: 80(4), P. 360 - 360

Published: Feb. 8, 2023

Importance Comorbidities and genetic correlations between gastrointestinal tract diseases psychiatric disorders have been widely reported, with the gut-brain axis (GBA) hypothesized as a potential biological basis. However, degree to which shared determinants are involved in these associations underlying GBA is unclear. Objective To investigate etiology identify genomic loci, genes, pathways. Design, Setting, Participants This genome-wide pleiotropic association study using summary statistics from publicly available data sources was performed various statistical approaches sequentially single-nucleotide variation (SNV; formerly polymorphism [SNP]), gene levels pathways disentangle 4 (inflammatory bowel disease, irritable syndrome, peptic ulcer gastroesophageal reflux disease) 6 (schizophrenia, bipolar disorder, major depressive attention-deficit/hyperactivity posttraumatic stress anorexia nervosa). Data were collected March 10, 2021, August 25, analysis January 8 through May 30, 2022. Main Outcomes Measures The primary outcomes consisted of list disorders. Results Extensive overlaps found among 22 24 trait pairs. Pleiotropic under composite null hypothesis identified 2910 significant SNVs 19 pairs, 83 loci colocalized detected. Gene-based 158 unique candidate highly enriched certain GBA-related phenotypes tissues, whereas pathway enrichment further highlighted primarily involving cell adhesion, synaptic structure function, immune differentiation. Several also causal variants gut microbiomes. Mendelian randomization illustrated vertical pleiotropy across pairwise traits. Notably, many for multiple traits, such 1q32.1 ( INAVA ), 19q13.33 FUT2 11q23.2 NCAM1 1p32.3 LRP8 ). Conclusions Relevance These findings suggest that extensively distributed genome. not only support basis but important implications intervention treatment targets simultaneously.

Language: Английский

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Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(12), P. 3184 - 3192

Published: Dec. 1, 2023

Abstract Problematic alcohol use (PAU), a trait that combines disorder and alcohol-related problems assessed with questionnaire, is leading cause of death morbidity worldwide. Here we conducted large cross-ancestry meta-analysis PAU in 1,079,947 individuals (European, N = 903,147; African, 122,571; Latin American, 38,962; East Asian, 13,551; South 1,716 ancestries). We observed high degree cross-ancestral similarity the genetic architecture identified 110 independent risk variants within- analyses. Cross-ancestry fine mapping improved identification likely causal variants. Prioritizing genes through gene expression chromatin interaction brain tissues multiple associated PAU. existing medications for potential pharmacological studies by computational drug repurposing analysis. polygenic scores showed better performance association samples than single-ancestry scores. Genetic correlations between other traits were ancestries, substance having highest correlations. This study advances our knowledge etiology PAU, these findings may bring possible clinical applicability genetics insights—together neuroscience, biology data science—closer.

Language: Английский

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Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(2), P. 222 - 233

Published: Jan. 4, 2024

Abstract Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples European ancestry. Here we report a multi-ancestry GWAS MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used range measures define included African (36% effective sample size), East Asian (26%) South (6%) ancestry Hispanic/Latin American participants (32%). The identified 53 significantly associated novel loci. For loci samples, fewer than expected were transferable other groups. Fine mapping benefited additional diversity. A transcriptome-wide study 205 genes. These findings suggest that, for increasing ancestral global diversity genetic may be particularly important ensure discovery core genes inform about transferability findings.

Language: Английский

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