scholarly journals A Phenome Wide Association Study of Severe COVID-19 Genetic Risk Variants

2021 ◽  
Author(s):  
Jessica A. Regan ◽  
Jawan Abdulrahim ◽  
Nathan Bihlmeyer ◽  
Carol Haynes ◽  
Lydia Coulter Kwee ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Risk ◽  
Risk Allele ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Genetic Loci ◽  
Psoriatic Arthropathy ◽  
Risk Alleles ◽  
Atrial Fibrillation And Flutter ◽  
The Uk

AbstractBackgroundGenetic loci associated with risk of severe COVID-19 infection have been identified and individuals with complicated COVID-19 infections often have multiple comorbidities.ObjectiveIdentify known and unidentified comorbidities associated with genetic loci linked to risk of severe COVID-19 infection.MethodsA Phenome Wide Association Study (PheWAS) was conducted in 247,448 unrelated, white individuals from the UK Biobank to test the association of 1,402 unique phenotypes with ten genome-wide significant severe-COVID risk single nucleotide polymorphisms (SNP) identified from prior studies. A validation PheWAS was conducted in 2,247 white individuals from the CATHGEN.ResultsFour of the ten tested genetic loci showed significant phenotypic associations in UK Biobank after FDR adjustment. Vascular dementia significantly associated with rs7271165 near TMEM65 on 8q24.13 in individuals with the C risk allele (OR 5.66 [95% CI 2.21-11.85], q=0.049). We identified 40 novel phenotype associations with rs657152 on 9q34.2 coinciding with the ABO gene with individuals with the A COVID risk allele having higher odds of heart failure (OR 1.09 [95% CI 1.03-1.14], q=0.004), diabetes mellitus (OR 1.05 [95% CI 1.02-1.07], q=0.004) and hypercholesterolemia (OR 1.04 [95% CI 1.02-1.06], q=6.3×10−5). Eight phenotypes associated with rs1819040 near KANSL1 on 17q21.31 in individuals with the A risk allele including atrial fibrillation and flutter (OR 1.07 [95% CI 1.04-1.10], q=0.0084) and pulmonary fibrosis (OR 0.80 [95% CI 0.71-0.89], q=0.035). Ten novel phenotypic associations were identified in association with rs74956615 on 19p13.2 near the TYK2 gene including individuals with the A COVID risk allele having lower odds of psoriatic arthropathy (OR 0.31 [95% CI 0.20-0.47], q=4.5×10−5), rheumatoid arthritis (OR 0.83 [95% CI 0.64-0.83], p=1.4×10−6) and thyrotoxicosis with or without goiter (OR 0.77 [95% CI 0.68-0.87], p-6.9×10−5). Two associations for rs1819040 (KANSL1) and seven associations for rs74956615 (TYK2) validated in CATHGEN.ConclusionsUsing a broad PheWAS approach in a large discovery and validation cohort, we have identified novel phenotypic associations with risk alleles for severe COVID-19 infection. Interestingly, the ABO locus was associated with comorbidities that are also risk factors for severe COVID-19 infection, suggesting that this locus has pleiotropic effects and provides a potential mechanism for this association. The 19p13 locus was associated with lower risk of autoimmune disease, these findings may have broad implications for the importance of multiple comorbidities across both infectious and non-infectious diseases and may provide insight in the molecular function of the genes near these genetic risk loci.

scholarly journals Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

2018 ◽  
Vol 49 (15) ◽  
pp. 2499-2504 ◽  
Author(s):  
Valentina Escott-Price ◽  
Daniel J. Smith ◽  
Kimberley Kendall ◽  
Joey Ward ◽  
George Kirov ◽  
...  
Keyword(s):  
Environmental Exposure ◽  
Copy Number Variants ◽  
Season Of Birth ◽  
Uk Biobank ◽  
Month Of Birth ◽  
Risk Alleles ◽  
Gene Environment ◽  
Increased Risk ◽  
The Uk ◽  
Pathogenic Process

AbstractBackgroundThere is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.MethodsHere we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.ResultsNeither genetic measure was associated with season or month of birth within the UKBB sample.ConclusionsAs our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.

scholarly journals Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse

2021 ◽  
Author(s):  
Mengyao Yu ◽  
Sergiy Kyryachenko ◽  
Stephanie Debette ◽  
Philippe Amouyel ◽  
Jean-Jacques Schott ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Cardiac Development ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Additional Risk ◽  
Genome Wide ◽  
The Uk

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank. Methods: We reanalyzed 1007/479 cases from the MVP-France study, 1469/862 controls from the MVP-Nantes study for reimputation genotypes using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-genome-wide association study annotations and MAGMA for gene-based and gene-set analyses. Results: We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1 . We identified an additional risk locus on Chr1 ( SYT2 ) and 2 suggestive risk loci on chr8 ( MSRA ) and chr19 ( FBXO46 ), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

scholarly journals Night Shift Work, Genetic Risk, and Type 2 Diabetes in the UK Biobank

Diabetes Care ◽  
2018 ◽  
Vol 41 (4) ◽  
pp. 762-769 ◽  
Author(s):  
Céline Vetter ◽  
Hassan S. Dashti ◽  
Jacqueline M. Lane ◽  
Simon G. Anderson ◽  
Eva S. Schernhammer ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Shift Work ◽  
Genetic Risk ◽  
Night Shift ◽  
Uk Biobank ◽  
Night Shift Work ◽  
The Uk

scholarly journals Identifying cross-disease components of genetic risk across hospital data in the UK Biobank

2019 ◽  
Vol 52 (1) ◽  
pp. 126-134 ◽  
Author(s):  
Adrian Cortes ◽  
Patrick K. Albers ◽  
Calliope A. Dendrou ◽  
Lars Fugger ◽  
Gil McVean
Keyword(s):  
Genetic Risk ◽  
Uk Biobank ◽  
Hospital Data ◽  
The Uk

scholarly journals Genetically downregulated interleukin-6 signaling is associated with a favorable cardiometabolic profile: a phenome-wide association study

2020 ◽  
Author(s):  
Marios K. Georgakis ◽  
Rainer Malik ◽  
Xue Li ◽  
Dipender Gill ◽  
Michael G. Levin ◽  
...  
Keyword(s):  
Association Study ◽  
Clinical Outcomes ◽  
Interleukin 6 ◽  
Lower Risk ◽  
Bacterial Infections ◽  
Interleukin 4 ◽  
Uk Biobank ◽  
The Uk ◽  
Tract Infections ◽  
Cardiometabolic Profile

AbstractBackgroundInterleukin-6 (IL6) signaling is a key inflammatory pathway widely implicated in the pathogenesis of multiple diseases including autoimmune, vascular, and metabolic disorders. While IL6-receptor (IL6R) inhibitors are already in use for the treatment of autoimmune diseases, their repurposing potential and safety profile is still debated.MethodsWe used 7 genetic variants at the IL6R locus as proxies for IL6 signaling downregulation and explored their effects on 1,428 clinical outcomes in a phenome-wide association study (PheWAS) using data from the UK Biobank (339,256 unrelated individuals). Significant associations were meta-analyzed with data from the Penn Medicine (10,244 individuals) and BioMe (9,054 individuals) Biobanks for validation. We further investigated associations between genetically downregulated IL6 signaling and 366 biomarkers and endophenotypes of human disease in the UK Biobank and other phenotype-specific consortia. All associations were examined by Mendelian randomization (MR) analyses scaled to the effects of tocilizumab, a monoclonal antibody targeting IL6R.ResultsThe PheWAS-MR analyses showed significant associations with 16 clinical outcomes and 17 biomarkers following correction for multiple comparisons. Genetically downregulated IL6 signaling was associated with a lower risk of several atherosclerotic phenotypes including ischemic heart disease (OR: 0.84, 95%CI: 0.77-0.90) and abdominal aortic aneurysm (OR: 0.44, 95%CI: 0.29-0.67). We further found significant associations with lower risk of type 2 diabetes (OR: 0.80, 95%CI: 0.73-0.88), lower glycated hemoglobin A1c (HbA1c) levels (beta: −0.07, 95%CI: −0.08 to −0.05), and higher HDL-cholesterol levels (beta: 0.04, 95%CI: 0.02-0.06). In accord with clinical trials examining pharmacological IL6 blockade, genetically downregulated IL6 signaling was associated with higher risk of neutropenia and bacterial infections (cellulitis and urinary tract infections) and with higher hemoglobin concentrations. We further found significant associations with higher risk of atopic dermatitis and higher levels of the pro-allergic cytokine interleukin-4.ConclusionsGenetic IL6 signaling downregulation associates with a lower risk of vascular outcomes and a more favorable cardiometabolic profile. These findings further support a repurposing of IL6R blockade for lowering cardiovascular risk while also informing on potential side effects.

scholarly journals Unhealthy Lifestyle, Genetics and Risk of Cardiovascular Disease and Mortality in 76,958 Individuals from the UK Biobank Cohort Study

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4283
Author(s):  
Katherine M. Livingstone ◽  
Gavin Abbott ◽  
Joey Ward ◽  
Steven J. Bowe
Keyword(s):  
Cardiovascular Disease ◽  
Cohort Study ◽  
Polygenic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Unhealthy Lifestyle ◽  
Hazard Ratios ◽  
All Cause Mortality ◽  
The Uk ◽  
Cvd Mortality

To examine associations of unhealthy lifestyle and genetics with risk of all-cause mortality, cardiovascular disease (CVD) mortality, myocardial infarction (MI) and stroke. We used data on 76,958 adults from the UK Biobank prospective cohort study. Favourable lifestyle included no overweight/obesity, not smoking, physical activity, not sedentary, healthy diet and adequate sleep. A Polygenic Risk Score (PRS) was derived using 300 CVD-related single nucleotide polymorphisms. Cox proportional hazard ratios (HR) were used to model effects of lifestyle and PRS on risk of CVD and all-cause mortality, stroke and MI. New CVD (n = 364) and all-cause (n = 2408) deaths, and stroke (n = 748) and MI (n = 1140) events were observed during a 7.8 year mean follow-up. An unfavourable lifestyle (0–1 healthy behaviours) was associated with higher risk of all-cause mortality (HR: 2.06; 95% CI: 1.73, 2.45), CVD mortality (HR: 2.48; 95% CI: 1.64, 3.76), MI (HR: 2.12; 95% CI: 1.65, 2.72) and stroke (HR:1.74; 95% CI: 1.25, 2.43) compared to a favourable lifestyle (≥4 healthy behaviours). PRS was associated with MI (HR: 1.35; 95% CI: 1.27, 1.43). There was evidence of a lifestyle-genetics interaction for stroke (p = 0.017). Unfavourable lifestyle behaviours predicted higher risk of all-cause mortality, CVD mortality, MI and stroke, independent of genetic risk.

Sign in / Sign up

Export Citation Format

Share Document