scholarly journals Analysis of 200,000 exome-sequenced UK Biobank subjects implicates genes involved in increased and decreased risk of hypertension

2021 ◽  
Author(s):  
David Curtis
Keyword(s):  
Rare Variants ◽  
Soluble Guanylate Cyclase ◽  
Therapeutic Interventions ◽  
Large Contribution ◽  
Protective Effects ◽  
Uk Biobank ◽  
Increased Risk ◽  
Higher Weights ◽  
The Uk ◽  
Diagnosis Of Hypertension

AbstractBackgroundPrevious analyses have identified common variants along with some specific genes and rare variants which are associated with risk of hypertension but much remains to be discovered.Methods and ResultsExome-sequenced UK Biobank participants were phenotyped based on having a diagnosis of hypertension or taking anti-hypertensive medication to produce a sample of 66,123 cases and 134,504 controls. Variants with minor allele frequency (MAF) < 0.01 were subjected to a gene-wise weighted burden analysis, with higher weights assigned to variants which are rarer and/or predicted to have more severe effects. Of 20,384 genes analysed, two genes were exome-wide significant,DNMT3AandFES. Also strongly implicated wereGUCY1A1andGUCY1B1, which code for the subunits of soluble guanylate cyclase. There was further support for the previously reported effects of variants inNPR1and protective effects of variants inDBH. An inframe deletion inCACNA1Dwith MAF = 0.005, rs72556363, is associated with modestly increased risk of hypertension. Other biologically plausible genes highlighted consist ofCSK, AGTR1, ZYXandPREP. All variants implicated were rare and cumulatively they are not predicted to make a large contribution to the population risk of hypertension.ConclusionsThis approach confirms and clarifies previously reported findings and also offers novel insights into biological processes influencing hypertension risk, potentially facilitating the development of improved therapeutic interventions. This research has been conducted using the UK Biobank Resource.

scholarly journals Analysis of 200,000 Exome-Sequenced UK Biobank Subjects Implicates Genes Involved in Increased and Decreased Risk of Hypertension

Pulse ◽  
2021 ◽  
pp. 1-13
Author(s):  
David Curtis
Keyword(s):  
Rare Variants ◽  
Soluble Guanylate Cyclase ◽  
Therapeutic Interventions ◽  
Large Contribution ◽  
Protective Effects ◽  
Uk Biobank ◽  
Increased Risk ◽  
Higher Weights ◽  
The Uk ◽  
Diagnosis Of Hypertension

<b><i>Background:</i></b> Previous analyses have identified common variants along with some specific genes and rare variants which are associated with risk of hypertension, but much remains to be discovered. <b><i>Methods and Results:</i></b> Exome-sequenced UK Biobank participants were phenotyped based on having a diagnosis of hypertension or taking anti-hypertensive medication to produce a sample of 66,123 cases and 134,504 controls. Variants with minor allele frequency (MAF) &#x3c;0.01 were subjected to a gene-wise weighted burden analysis, with higher weights assigned to variants which are rarer and/or predicted to have more severe effects. Of 20,384 genes analysed, 2 genes were exome-wide significant, <i>DNMT3A</i> and <i>FES</i>. Also strongly implicated were <i>GUCY1A1</i> and <i>GUCY1B1</i>, which code for the subunits of soluble guanylate cyclase. There was further support for the previously reported effects of variants in <i>NPR1</i> and protective effects of variants in <i>DBH</i>. An inframe deletion in <i>CACNA1D</i> with MAF = 0.005, rs72556363, is associated with modestly increased risk of hypertension. Other biologically plausible genes highlighted consist of <i>CSK</i>, <i>AGTR1</i>, <i>ZYX</i>, and <i>PREP</i>. All variants implicated were rare, and cumulatively they are not predicted to make a large contribution to the population risk of hypertension. <b><i>Conclusions:</i></b> This approach confirms and clarifies previously reported findings and also offers novel insights into biological processes influencing hypertension risk, potentially facilitating the development of improved therapeutic interventions. This research has been conducted using the UK Biobank Resource.

scholarly journals Rare GATA6 variants associated with risk of congenital heart disease phenotypes in 200,000 UK Biobank exomes

2021 ◽  
Author(s):  
Simon G Williams ◽  
Dominic Byrne ◽  
Bernard Keavney
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Rare Variants ◽  
Uk Biobank ◽  
Sequencing Data ◽  
Chd Risk ◽  
Increased Risk ◽  
Sequencing Studies ◽  
The Uk

Several genes have been associated with congenital heart disease (CHD) risk in previous GWAS and sequencing studies, but studies involving larger numbers of case samples remain needed to facilitate further understanding of what remains a complex and largely uncharacterised genetic etiology. Here we use whole exome sequencing data from 200,000 samples in the UK Biobank to assess ultra-rare and potentially pathogenic variation associated with increased risk of CHD. Our findings indicate that rare variants in GATA6, presumably with a lesser effect on gene function than those causing severe CHD phenotypes, or buffered by other genetic and environmental effects during development, are also associated with minor CHD conditions, specifically bicuspid aortic valve, the most common CHD condition.

scholarly journals The Association of Age at Diagnosis of Hypertension With Brain Structure and Incident Dementia in the UK Biobank

Hypertension ◽  
2021 ◽  
Author(s):  
Xianwen Shang ◽  
Edward Hill ◽  
Zhuoting Zhu ◽  
Jiahao Liu ◽  
B. Zongyuan Ge ◽  
...  
Keyword(s):  
Gray Matter ◽  
Brain Volume ◽  
Multivariable Analysis ◽  
Brain Magnetic Resonance Imaging ◽  
Hospital Inpatient ◽  
Uk Biobank ◽  
Brain Volumes ◽  
Increased Risk ◽  
The Uk ◽  
Diagnosis Of Hypertension

Little is known about whether the association of hypertension with brain volume and dementia is modified by an individual’s age at their diagnosis of hypertension. Our analysis was based on the UK Biobank with baseline data collected between 2006 and 2010. Brain magnetic resonance imaging was used to measure brain volumes between 2014 and 2019. Dementia was ascertained using hospital inpatient, mortality, and self-reported data until 2021. We randomly selected a control participant for each hypertensive participant stratified by hypertension diagnosis age using propensity score. The cohort comprised 11 399 individuals with hypertension and 11 399 controls for the brain volume analysis and 124 053 individuals with hypertension and 124 053 controls for the dementia analysis. Individuals with hypertension diagnosed at ages <35 (β (95% CI, −10.83 [−19.27 to −2.39] mL), 35 to 44 (−6.82 [−12.18 to −1.46] mL), and 45 to 54 years (−3.77 [−6.91 to −0.64] mL) had smaller total brain volume compared with the corresponding controls in the multivariable analysis. Similarly, hypertension diagnosed in early- and mid-life was independently associated with smaller volumes of gray matter, peripheral cortical gray matter, and white matter. Over a median follow-up of 11.9 years, 4626 cases of incident all-cause dementia were documented. Individuals with hypertension diagnosed at 35 to 44 years of age only (hazard ratio [95% CI]: 1.61 [1.31–1.99]) had a higher risk of all-cause dementia compared with the corresponding controls after adjustment for covariates. Hypertension diagnosed in young adulthood or mid-life, but not late life is associated with smaller brain volumes and an increased risk of dementia.

scholarly journals Socioeconomic Inequalities and Ethnicity Are Associated with a Positive COVID-19 Test among Cancer Patients in the UK Biobank Cohort

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1514
Author(s):  
Shing Fung Lee ◽  
Maja Nikšić ◽  
Bernard Rachet ◽  
Maria-Jose Sanchez ◽  
Miguel Angel Luque-Fernandez
Keyword(s):  
Cancer Patients ◽  
Socioeconomic Inequalities ◽  
Uk Biobank ◽  
Incident Cancer ◽  
Increased Risk ◽  
Exposure Variable ◽  
Independent Risk Factors ◽  
The Uk ◽  
Deprived Areas

We explored the role of socioeconomic inequalities in COVID-19 incidence among cancer patients during the first wave of the pandemic. We conducted a case-control study within the UK Biobank cohort linked to the COVID-19 tests results available from 16 March 2020 until 23 August 2020. The main exposure variable was socioeconomic status, assessed using the Townsend Deprivation Index. Among 18,917 participants with an incident malignancy in the UK Biobank cohort, 89 tested positive for COVID-19. The overall COVID-19 incidence was 4.7 cases per 1000 incident cancer patients (95%CI 3.8–5.8). Compared with the least deprived cancer patients, those living in the most deprived areas had an almost three times higher risk of testing positive (RR 2.6, 95%CI 1.1–5.8). Other independent risk factors were ethnic minority background, obesity, unemployment, smoking, and being diagnosed with a haematological cancer for less than five years. A consistent pattern of socioeconomic inequalities in COVID-19 among incident cancer patients in the UK highlights the need to prioritise the cancer patients living in the most deprived areas in vaccination planning. This socio-demographic profiling of vulnerable cancer patients at increased risk of infection can inform prevention strategies and policy improvements for the coming pandemic waves.

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 Assessing the contribution of rare-to-common protein-coding variants to circulating metabolic biomarker levels via 412,394 UK Biobank exome sequences

2021 ◽  
Author(s):  
Abhishek Nag ◽  
Lawrence Middleton ◽  
Ryan S Dhindsa ◽  
Dimitrios Vitsios ◽  
Eleanor M Wigmore ◽  
...  
Keyword(s):  
Gene Networks ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Protein Coding ◽  
The Uk ◽  
Metabolic Biomarkers ◽  
Coding Variants

Genome-wide association studies have established the contribution of common and low frequency variants to metabolic biomarkers in the UK Biobank (UKB); however, the role of rare variants remains to be assessed systematically. We evaluated rare coding variants for 198 metabolic biomarkers, including metabolites assayed by Nightingale Health, using exome sequencing in participants from four genetically diverse ancestries in the UKB (N=412,394). Gene-level collapsing analysis, that evaluated a range of genetic architectures, identified a total of 1,303 significant relationships between genes and metabolic biomarkers (p<1x10-8), encompassing 207 distinct genes. These include associations between rare non-synonymous variants in GIGYF1 and glucose and lipid biomarkers, SYT7 and creatinine, and others, which may provide insights into novel disease biology. Comparing to a previous microarray-based genotyping study in the same cohort, we observed that 40% of gene-biomarker relationships identified in the collapsing analysis were novel. Finally, we applied Gene-SCOUT, a novel tool that utilises the gene-biomarker association statistics from the collapsing analysis to identify genes having similar biomarker fingerprints and thus expand our understanding of gene networks.

scholarly journals Associations of cigarette smoking with gray and white matter in the UK Biobank

2019 ◽  
Author(s):  
Joshua Gray ◽  
Matthew Thompson ◽  
Chelsie Benca-Bachman ◽  
Max Michael Owens ◽  
Mikela Murphy ◽  
...  
Keyword(s):  
White Matter ◽  
Cigarette Smoking ◽  
Gray Matter ◽  
Brain Structure ◽  
Mean Diffusivity ◽  
Medial Lemniscus ◽  
Uk Biobank ◽  
Matter Volume ◽  
Increased Risk ◽  
The Uk

Chronic cigarette smoking is associated with increased risk for myriad health consequences including cognitive decline and dementia, but research on the link between smoking and brain structure is nascent. We assessed the relationship of cigarette smoking (ever smoked, cigarettes per day, and duration) with gray and white matter using the UK Biobank cohort (gray matter N = 19,615; white matter N = 17,760), adjusting for numerous demographic and health confounders. Ever smoked and duration were associated with smaller total gray matter volume. Ever smoked was associated with reduced volume of the right VIIIa cerebellum, as well as elevated white matter hyperintensity volumes. Smoking duration was associated with reduced total white matter volume. With regard to specific tracts, ever smoked was associated with reduced fractional anisotropy in the left cingulate gyrus part of the cingulum, left posterior thalamic radiation, and bilateral superior thalamic radiation and increased mean diffusivity in the middle cerebellar peduncle, right medial lemniscus, bilateral posterior thalamic radiation, and bilateral superior thalamic radiation. Overall, we found significant associations of cigarette exposure with global measures of gray and white matter. Furthermore, we found select associations of ever smoked, but not cigarettes per day or duration, with specific gray and white matter regions. These findings inform our understanding of the connections between smoking and variation in brain structure and clarify potential mechanisms of risk for common neurological sequelae.

scholarly journals Diabetes, glycated haemoglobin and the risk of myocardial infarction in women and men: a prospective cohort study of the UK Biobank

2020 ◽  
Author(s):  
Marit de Jong ◽  
Mark Woodward ◽  
Sanne A.E Peters
Keyword(s):  
Myocardial Infarction ◽  
Sex Differences ◽  
Glycated Haemoglobin ◽  
Incidence Rates ◽  
Undiagnosed Diabetes ◽  
Uk Biobank ◽  
Diabetes Status ◽  
Increased Risk ◽  
The Uk ◽  
Diagnosed Diabetes

<b>Objective:</b> Diabetes has shown to be a stronger risk factor for myocardial infarction (MI) in women than men. Whether sex differences exist across the glycaemic spectrum is unknown. We investigated sex differences in the associations of diabetes status and glycated haemoglobin (HbA1c) with the risk of MI. <br> <b>Research Design and Methods:</b> Data were used from 471,399 (56% women) individuals without cardiovascular disease (CVD) included in the UK Biobank. Sex-specific incidence rates were calculated by diabetes status and across levels of HbA1c, using Poisson regression. Cox proportional hazards analyses estimated sex-specific hazard ratios (HR) and women-to-men ratios by diabetes status and HbA1c for MI during a mean follow-up of 9 years. <br> <b>Results:</b> Women had lower incidence rates of MI than men, regardless of diabetes status or HbA1c level. Compared with individuals without diabetes, prediabetes, undiagnosed diabetes, and previously diagnosed diabetes were associated with increased risk of MI in both sexes. Previously diagnosed diabetes was more strongly associated with MI in women (HR 2∙33 [95%CI 1∙96;2∙78]) than men (1∙81 [1∙63;2∙02]), with a women-to-men ratio of HRs of 1∙29 (1∙05;1∙58). Each 1% higher HbA1c, independent of diabetes status, was associated with an 18% greater risk of MI in both women and men.<br> <b>Conclusions:</b> Although the incidence of MI was higher in men than women, the presence of diabetes is associated with a greater excess relative risk of MI in women. However, each 1% higher HbA1c was associated with an 18% greater risk of MI in both women and men.<br> <br>

scholarly journals Diabetes, glycated haemoglobin and the risk of myocardial infarction in women and men: a prospective cohort study of the UK Biobank

2020 ◽  
Author(s):  
Marit de Jong ◽  
Mark Woodward ◽  
Sanne A.E Peters
Keyword(s):  
Myocardial Infarction ◽  
Sex Differences ◽  
Glycated Haemoglobin ◽  
Incidence Rates ◽  
Undiagnosed Diabetes ◽  
Uk Biobank ◽  
Diabetes Status ◽  
Increased Risk ◽  
The Uk ◽  
Diagnosed Diabetes

<b>Objective:</b> Diabetes has shown to be a stronger risk factor for myocardial infarction (MI) in women than men. Whether sex differences exist across the glycaemic spectrum is unknown. We investigated sex differences in the associations of diabetes status and glycated haemoglobin (HbA1c) with the risk of MI. <br> <b>Research Design and Methods:</b> Data were used from 471,399 (56% women) individuals without cardiovascular disease (CVD) included in the UK Biobank. Sex-specific incidence rates were calculated by diabetes status and across levels of HbA1c, using Poisson regression. Cox proportional hazards analyses estimated sex-specific hazard ratios (HR) and women-to-men ratios by diabetes status and HbA1c for MI during a mean follow-up of 9 years. <br> <b>Results:</b> Women had lower incidence rates of MI than men, regardless of diabetes status or HbA1c level. Compared with individuals without diabetes, prediabetes, undiagnosed diabetes, and previously diagnosed diabetes were associated with increased risk of MI in both sexes. Previously diagnosed diabetes was more strongly associated with MI in women (HR 2∙33 [95%CI 1∙96;2∙78]) than men (1∙81 [1∙63;2∙02]), with a women-to-men ratio of HRs of 1∙29 (1∙05;1∙58). Each 1% higher HbA1c, independent of diabetes status, was associated with an 18% greater risk of MI in both women and men.<br> <b>Conclusions:</b> Although the incidence of MI was higher in men than women, the presence of diabetes is associated with a greater excess relative risk of MI in women. However, each 1% higher HbA1c was associated with an 18% greater risk of MI in both women and men.<br> <br>

scholarly journals Analysis of exome-sequenced UK Biobank subjects implicates genes affecting risk of hyperlipidaemia

2020 ◽  
Author(s):  
David Curtis
Keyword(s):  
Rare Variants ◽  
Sequence Data ◽  
Lipid Lowering ◽  
P Value ◽  
Data Sets ◽  
Uk Biobank ◽  
Functional Studies ◽  
Exome Sequence Data ◽  
Rare Genetic Variants ◽  
The Uk

Rare genetic variants in LDLR, APOB and PCSK9 are known causes of familial hypercholesterolaemia and it is expected that rare variants in other genes will also have effects on hyperlipidaemia risk although such genes remain to be identified. The UK Biobank consists of a sample of 500,000 volunteers and exome sequence data is available for 50,000 of them. 11,490 of these were classified as hyperlipidaemia cases on the basis of having a relevant diagnosis recorded and/or taking lipid-lowering medication while the remaining 38,463 were treated as controls. Variants in each gene were assigned weights according to rarity and predicted impact and overall weighted burden scores were compared between cases and controls, including population principal components as covariates. One biologically plausible gene, HUWE1, produced statistically significant evidence for association after correction for testing 22,028 genes with a signed log10 p value (SLP) of -6.15, suggesting a protective effect of variants in this gene. Other genes with uncorrected p<0.001 are arguably also of interest, including LDLR (SLP=3.67), RBP2 (SLP=3.14), NPFFR1 (SLP=3.02) and ACOT9 (SLP=-3.19). Gene set analysis indicated that rare variants in genes involved in metabolism and energy can influence hyperlipidaemia risk. Overall, the results provide some leads which might be followed up with functional studies and which could be tested in additional data sets as these become available. This research has been conducted using the UK Biobank Resource.

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