scholarly journals 649Personal history of keratinocyte carcinoma is a marker of inherited cancer risk: Mendelian randomization analyses

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Jean Claude Dusingize ◽  
Catherine Olsen ◽  
Jiyuan An ◽  
Upekha Liyanage ◽  
Nirmala Pandeya ◽  
...  
Keyword(s):  
Risk Factor ◽  
Cancer Risk ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Personal History ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Inherited Cancer ◽  
History Of ◽  
The Uk

Abstract Background A personal history of keratinocyte carcinoma (KC) has been reported as a risk factor for developing subsequent primary cutaneous and non-cutaneous malignancies. However most evidence to date stems from observational studies which are prone to bias, confounding and reverse causation. Our aim was to examine this association using different Mendelian randomization (MR) approaches. Methods We performed a one-sample MR analysis using individual-level data from the UK Biobank (n = 394,306). This analysis was then validated in an independent dataset in the QSkin cohort (n = 16,896). Using 64 independent genetic variants known to be associated with KC, we generated a polygenic risk score (PRS) for each participant in the UK Biobank and the QSkin cohort. We then performed two-sample MR analyses using genome-wide association study (GWAS) summary statistics. We tested the association between genetically predicted KC and risk of subsequent cancer using logistic regression. Results Results from one-sample MR analyses in the UK Biobank indicated that a personal history of KC was significantly associated with cancer overall (excluding melanoma) (OR: 1.15, 95% CI: 1.10-1.20, per doubling the prevalence of KC). The results from the two-sample MR corroborate the findings from the one-sample MR, although the risk estimate was lower (OR: 1.05, 95% CI: 1.03-1.07). Conclusions Our MR analyses suggest that genetically predicted KC is a risk factor for developing subsequent primary malignancies. Key messages A personal history of KC may serve as a proxy marker of inherited cancer risk.

Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study

2021 ◽  
Author(s):  
Christa Meisinger ◽  
Dennis Freuer
Keyword(s):  
Inflammatory Bowel Disease ◽  
Atopic Dermatitis ◽  
Bowel Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
The Other ◽  
Uk Biobank ◽  
Inflammatory Bowel ◽  
The Uk

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

scholarly journals Bilirubin is not associated with urinary bladder cancer risk and prognosis: A Mendelian Randomization Study in the UK Biobank

2020 ◽  
Author(s):  
Nadezda Lipunova ◽  
Richard T Bryan ◽  
Maurice P Zeegers
Keyword(s):  
Bladder Cancer ◽  
Urinary Bladder ◽  
Cancer Risk ◽  
Mendelian Randomization ◽  
Smoking Status ◽  
Urinary Bladder Cancer ◽  
Potential Effect ◽  
Uk Biobank ◽  
Bladder Cancer Risk ◽  
The Uk

Mutations in UGT1A gene have been associated with the development and prognosis of urinary bladder cancer (UBC). UGT1A proteins are involved in a spectrum of detoxification processes, hence the biological mechanism between UGT1A and UBC is difficult to elucidate. Concurrently, mild hyperbilirubinemia, caused by alterations in UGT1A, has been associated with multiple health outcomes. We have investigated the potential effect of mild hyperbilirubinemia on UBC risk and prognosis, using a Mendelian Randomization (MR) approach in the UK Biobank. Data on 1,281 UBC patients and 4,071 controls was available for a two-stage least squares MR estimation with rs6742078 as an instrumental variable. First, linear regression was fitted to establish the relationship between the rs6742078 and bilirubin levels (total and unconjugated). Secondly, bilirubin values were used to predict tested outcomes under a logistic model. Both stages were adjusted for participant sex, smoking status, and age. MR analysis showed no significant effects of bilirubin levels on UBC risk (total bilirubin: OR=1.02, 95% CI: 0.99-1.04; unconjugated bilirubin: OR=1.02, 95% CI: 0.99-1.05). No effects were observed for events of UBC recurrence, progression, or survival. Our study suggests mild hyperbilirubinemia is not associated with urinary bladder cancer risk and prognosis.

scholarly journals Polygenic Risk Score Prediction for Endometriosis

2021 ◽  
Vol 3 ◽  
Author(s):  
Kirstine Kloeve-Mogensen ◽  
Palle Duun Rohde ◽  
Simone Twisttmann ◽  
Marianne Nygaard ◽  
Kristina Magaard Koldby ◽  
...  
Keyword(s):  
Risk Score ◽  
Genome Wide Association Study ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Standard Deviation Increase ◽  
Polygenic Risk ◽  
Clinical Risk ◽  
Risk Variants ◽  
Increased Risk ◽  
The Uk

Endometriosis is a major health care challenge because many young women with endometriosis go undetected for an extended period, which may lead to pain sensitization. Clinical tools to better identify candidates for laparoscopy-guided diagnosis are urgently needed. Since endometriosis has a strong genetic component, there is a growing interest in using genetics as part of the clinical risk assessment. The aim of this work was to investigate the discriminative ability of a polygenic risk score (PRS) for endometriosis using three different cohorts: surgically confirmed cases from the Western Danish endometriosis referral Center (249 cases, 348 controls), cases identified from the Danish Twin Registry (DTR) based on ICD-10 codes from the National Patient Registry (140 cases, 316 controls), and replication analysis in the UK Biobank (2,967 cases, 256,222 controls). Patients with adenomyosis from the DTR (25 cases) and from the UK Biobank (1,883 cases) were included for comparison. The PRS was derived from 14 genetic variants identified in a published genome-wide association study with more than 17,000 cases. The PRS was associated with endometriosis in surgically confirmed cases [odds ratio (OR) = 1.59, p = 2.57× 10−7] and in cases from the DTR biobank (OR = 1.50, p = 0.0001). Combining the two Danish cohorts, each standard deviation increase in PRS was associated with endometriosis (OR = 1.57, p = 2.5× 10−11), as well as the major subtypes of endometriosis; ovarian (OR = 1.72, p = 6.7× 10−5), infiltrating (OR = 1.66, p = 2.7× 10−9), and peritoneal (OR = 1.51, p = 2.6 × 10−3). These findings were replicated in the UK Biobank with a much larger sample size (OR = 1.28, p < 2.2× 10−16). The PRS was not associated with adenomyosis, suggesting that adenomyosis is not driven by the same genetic risk variants as endometriosis. Our results suggest that a PRS captures an increased risk of all types of endometriosis rather than an increased risk for endometriosis in specific locations. Although the discriminative accuracy is not yet sufficient as a stand-alone clinical utility, our data demonstrate that genetics risk variants in form of a simple PRS may add significant new discriminatory value. We suggest that an endometriosis PRS in combination with classical clinical risk factors and symptoms could be an important step in developing an urgently needed endometriosis risk stratification tool.

scholarly journals Blood Pressure and Risk of Cardiovascular Disease in UK Biobank

Hypertension ◽  
2021 ◽  
Author(s):  
Eric Yuk Fai Wan ◽  
Wing Tung Fung ◽  
C. Mary Schooling ◽  
Shiu Lun Au Yeung ◽  
Man Ki Kwok ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Randomization Test ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Causal Association ◽  
Uk Biobank ◽  
Cvd Risk ◽  
The Uk

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25–1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15–1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24–1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14–1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24–1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12–1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.

scholarly journals Machine Learning to Understand Genetic and Clinical Factors Associated with the Pulse Waveform Dicrotic Notch

2021 ◽  
Author(s):  
Jonathan W. Cunningham ◽  
Paolo Di Achille ◽  
Valerie N. Morrill ◽  
Lu-Chen Weng ◽  
Seung Hoan Choi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Genome Wide Association Study ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Continuous Trait ◽  
Dicrotic Notch ◽  
Digital Phenotyping ◽  
A Genome ◽  
The Uk

AbstractBackgroundAbsence of a dicrotic notch on finger photoplethysmography (PPG) is an easily ascertainable and inexpensive trait that has been associated with age and prevalent cardiovascular disease (CVD). However, the trait exists along a continuum, and little is known about its genetic underpinnings or prognostic value for incident CVD.MethodsIn 169,787 participants in the UK Biobank, we identified absent dicrotic notch on PPG and created a novel continuous trait reflecting notch smoothness using machine learning. Next, we determined the heritability, genetic basis, polygenic risk, and clinical relations for the binary absent notch trait and the newly derived continuous notch smoothness trait.ResultsHeritability of the continuous notch smoothness trait was 7.5%, compared with 5.6% for the binary absent notch trait. A genome wide association study of notch smoothness identified 15 significant loci, implicating genes including NT5C2 (P=1.2×10−26), IGFBP3 (P=4.8×10−18), and PHACTR1 (P=1.4×10−13), compared with 6 loci for the binary absent notch trait. Notch smoothness stratified risk of incident myocardial infarction or coronary artery disease, stroke, heart failure, and aortic stenosis. A polygenic risk score for notch smoothness was associated with incident CVD and all-cause death in UK Biobank participants without available PPG data.ConclusionWe found that a machine learning derived continuous trait reflecting dicrotic notch smoothness on PPG was heritable and associated with genes involved in vascular stiffness. Greater notch smoothness was associated with greater risk of incident CVD. Raw digital phenotyping may identify individuals at risk for disease via specific genetic pathways.

scholarly journals Ability of known colorectal cancer susceptibility SNPs to predict colorectal cancer risk: A cohort study within the UK Biobank

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0251469
Author(s):  
Aviv Gafni ◽  
Gillian S. Dite ◽  
Erika Spaeth Tuff ◽  
Richard Allman ◽  
John L. Hopper
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Cancer Risk ◽  
Risk Model ◽  
Lifetime Risk ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Combined Model ◽  
Polygenic Risk ◽  
The Uk

Colorectal cancer risk stratification is crucial to improve screening and risk-reducing recommendations, and consequently do better than a one-size-fits-all screening regimen. Current screening guidelines in the UK, USA and Australia focus solely on family history and age for risk prediction, even though the vast majority of the population do not have any family history. We investigated adding a polygenic risk score based on 45 single-nucleotide polymorphisms to a family history model (combined model) to quantify how it improves the stratification and discriminatory performance of 10-year risk and full lifetime risk using a prospective population-based cohort within the UK Biobank. For both 10-year and full lifetime risk, the combined model had a wider risk distribution compared with family history alone, resulting in improved risk stratification of nearly 2-fold between the top and bottom risk quintiles of the full lifetime risk model. Importantly, the combined model can identify people (n = 72,019) who do not have family history of colorectal cancer but have a predicted risk that is equivalent to having at least one affected first-degree relative (n = 44,950). We also confirmed previous findings by showing that the combined full lifetime risk model significantly improves discriminatory accuracy compared with a simple family history model 0.673 (95% CI 0.664–0.682) versus 0.666 (95% CI 0.657–0.675), p = 0.0065. Therefore, a combined polygenic risk score and first-degree family history model could be used to improve risk stratified population screening programs.

scholarly journals Genome-wide association study of skin and soft tissue infection susceptibility

2020 ◽  
Author(s):  
Tormod Rogne ◽  
Kristin V Liyanarachi ◽  
Humaira Rasheed ◽  
Laurent F Thomas ◽  
Helene M Flatby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Soft Tissue ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Genome Wide Association ◽  
P Value ◽  
Uk Biobank ◽  
Genome Wide ◽  
Monocytes And Macrophages ◽  
The Uk

Background: Skin and soft tissue infections (SSTIs) are common worldwide, but little is known about the genetic susceptibility and the causal effect of cardiometabolic risk factors. We therefore conducted the first genome-wide association study (GWAS) of SSTIs, with downstream analyses including Mendelian randomization analyses. Methods: The GWAS was conducted using the UK Biobank as discovery cohort, with 6,107 cases and 399,239 controls, and the Trondelag Health Study (HUNT) as replication cohort with 1,657 cases and 67,522 controls. Cases and controls were those who had or had not been hospitalized with an SSTI diagnosis, respectively. Findings: One locus, lead single-nucleotide polymorphism rs3749748 in LINC01184/SLC12A2, was associated with SSTIs in the UK Biobank (odds ratio [OR] 1.19, p-value = 7.6e-16) and replicated in HUNT (OR 1.15, p-value = 6.3e-4). Meta-analysis confirmed the lead variant (OR 1.18, p-value = 4.4e-18), as well as suggested two additional loci close to genome-wide significance (rs2007361 in PSMA1, OR 0.91, p-value = 5.1e-8; and rs78625038 in GAN, OR 1.86, p-value = 5.9e-8). Gene-based association tests identified four genes linked to SSTIs: SLC12A2, PSMA1, GAN, and IL6R. The minor allele of rs3749748 reduced the gene expression of SLC12A2 primarily in monocytes and macrophages. Mendelian randomization analyses showed that increasing body mass index and lifetime smoking habits increased risk of SSTIs. Interpretation: LINC0118/SLC12A2 was robustly associated with SSTI incidence and may exert its effect through reduced gene expression in monocytes and macrophages. Reducing tobacco smoking, overweight and obesity in the population may reduce the incidence of SSTIs.

scholarly journals Ability of known colorectal cancer susceptibility SNPs to predict colorectal cancer risk: A cohort study within the UK Biobank

2021 ◽  
Author(s):  
Aviv Gafni ◽  
Gillian S. Dite ◽  
Erika Spaeth Tuff ◽  
Richard Allman ◽  
John L. Hopper
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Cancer Risk ◽  
Risk Model ◽  
Lifetime Risk ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Combined Model ◽  
Polygenic Risk ◽  
The Uk

AbstractColorectal cancer risk stratification is crucial to improve screening and risk-reducing recommendations, and consequently do better than a one-size-fits-all screening regimen. Current screening guidelines in the UK, USA and Australia focus solely on family history and age for risk prediction, even though the vast majority of the population do not have any family history. We investigated adding a polygenic risk score based on 45 single-nucleotide polymorphisms to a family history model (combined model) to quantify how it improves the stratification and discriminatory performance of 10-year risk and full lifetime risk using a prospective population-based cohort within the UK Biobank. For both 10-year and full lifetime risk, the combined model had a wider risk distribution compared with family history alone, resulting in improved risk stratification of nearly 2-fold between the top and bottom risk quintiles of the full lifetime risk model. Importantly, the combined model can identify people (n=72,019) who do not have family history of colorectal cancer but have a predicted risk that is equivalent to having at least one affected first-degree relative (n=44,950). We also confirmed previous findings by showing that the combined full lifetime risk model significantly improves discriminatory accuracy compared with a simple family history model 0.673 (95% CI 0.664–0.682 versus 0.666 (95% CI 0.657–0.675), p=0.0065. Therefore, a combined polygenic risk score and first-degree family history model could be used to improve risk stratified population screening programs.

scholarly journals Statin use in relation to intraocular pressure, glaucoma, and ocular coherence tomography parameters in the UK Biobank

2021 ◽  
Author(s):  
Jihye Kim ◽  
Marianne T. Kennedy Neary ◽  
Hugues Aschard ◽  
Mathew M. Palakkamanil ◽  
Ron Do ◽  
...  
Keyword(s):  
Layer Thickness ◽  
Regression Models ◽  
Genome Wide Association Study ◽  
Polygenic Risk Score ◽  
Inner Plexiform Layer ◽  
Uk Biobank ◽  
Linear Regression Models ◽  
Fiber Layer ◽  
The Uk ◽  
Statin Use

Objective: To evaluate the relationship between statin use and various glaucoma-related traits. Design: Cross-sectional analysis of UK Biobank data. Participants: We included 118,153 participants (mean age (SD)=56.8 (8.0) years) with data on statin use (5 statin types - 2006-2010) and corneal-compensated IOP measured in 2009-2013. Also, we included 192,283 participants (with 8,982 self-reported glaucoma cases as of 2006-2010) for the glaucoma analyses. After excluding participants with neurodegenerative diseases, 41,638 participants with global macular retinal nerve fiber layer thickness (mRNFL) and 41,547 participants with ganglion cell inner plexiform layer thickness (mGCIPL) measurements in 2009-2010 were available for analysis. Method: We examined associations with statin use utilizing multivariable-adjusted linear regression models for IOP, mRNFL, and mGCIPL and logistic regression models for glaucoma. We assessed whether a 2,673-member polygenic risk score (PRS) identified from a glaucoma multi-trait analysis of genome wide association study (MTAG) modified associations. We performed Mendelian randomization (MR) experiments using 5 gene variants as proxies for the cholesterol-altering effect of statins to investigate associations with various glaucoma-related outcomes. Main Outcome and Measures: IOP; glaucoma; mRNFL; mGCIPL. Results: Statin users had higher unadjusted mean IOP ± SD (16.3 ± 3.9 mm Hg; n = 20,593 participants) than non-users (15.9 ± 3.8 mm Hg; n = 97,560 participants), but in a multivariable-adjusted model, IOP did not differ by statin use (difference = 0.05 mm Hg; 95% CI: −0.02, 0.13; p=0.17). Similarly, statin use was not associated with prevalent glaucoma (OR = 1.05; 95% CI: 0.98, 1.13). Statin use was weakly associated with thinner mRNFL (difference = −0.15 microns; 95% CI: −0.28, -0.01; p=0.03) but not with mGCIPL thickness (difference = −0.12 microns; 95% CI: −0.29, 0.05; p=0.17). Among statins, simvastatin and atorvastatin, the two most commonly used statins, were not associated with any glaucoma outcome measures. No association was modified by the glaucoma MTAG PRS (Pinteraction≥0.16). MR experiments showed no evidence for a causal association between the cholesterol-altering effect of statins and various glaucoma outcomes (inverse weighted variance p≥0.14). Conclusions: Statin use was not associated with lower IOP, lower glaucoma prevalence, thicker mRNFL or thicker mGCIPL in the UK Biobank.

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