Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank

Background Red blood cell (RBC) transfusion and erythropoiesis‐stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obtained genetic variants predicting any of 12 RBC traits from the largest genome‐wide association study of hematological traits (173 480 participants of European ancestry) and applied them to the UK Biobank (265 424 white British participants). We used univariable mendelian randomization methods as sensitivity analyses for validation. Among 265 424 unrelated participants in the UK Biobank, there were 9752 cases of VTE (4490 men and 5262 women). Hemoglobin was selected as the plausible important RBC trait for VTE (marginal inclusion probability=0.91). The best‐fitting model across all RBC traits contained hemoglobin only (posterior probability=0.46). Using the inverse variance–weighted method, genetically predicted hemoglobin was positively associated (odds ratio, 1.21 per g/dL unit of hemoglobin; 95% CI, 1.05–1.41) with VTE. Sensitivity analyses (mendelian randomization–Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier test) gave consistent estimates. Conclusions Endogenous hemoglobin is the key RBC trait causing VTE, with a detrimental effect in the general population on VTE. Given men have higher hemoglobin than women, this finding may help explain the sexual disparity in VTE rates. The benefits of therapies and other factors that raise hemoglobin need to be weighed against their risks.

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Genetically-Determined Serum Calcium Levels and Markers of Ventricular Repolarisation: A Mendelian Randomization Study in the UK Biobank

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003231 ◽

2021 ◽

Author(s):

William J. Young ◽

Helen R. Warren ◽

Dennis O. Mook-Kanamori ◽

Julia Ramírez ◽

Stefan van Duijvenboden ◽

...

Keyword(s):

Serum Calcium ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Disease Risk ◽

Causal Effect ◽

Sensitivity Analyses ◽

European Ancestry ◽

Uk Biobank ◽

Ventricular Repolarisation ◽

Increased Risk

Background - Electrocardiographic (ECG) markers of ventricular depolarisation and repolarisation are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian Randomization (MR). Methods - Independent lead variants from a newly performed genome-wide association study (GWAS) for serum calcium in >300,000 European-ancestry participants from UK-Biobank were used as instrumental variables. Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT and QRS intervals using an inverse-weighted method in 76,226 participants not contributing to the serum calcium GWAS. Sensitivity analyses including MR-Egger, weighted-median estimator, and MR-PRESSO were performed to test for the presence of horizontal pleiotropy. Results - 205 independent lead calcium-associated variants were used as instrumental variables for MR. A decrease of 0.1 mmol/L serum calcium was associated with longer QT (3.01ms (95% CI 3.99, -2.03) and JT (2.89ms (-3.87, - 1.91) intervals. A weak association was observed for QRS duration (secondary analyses only). Results were concordant in all sensitivity analyses. Conclusions - These analyses support a causal effect of serum calcium levels on ventricular repolarisation, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may therefore directly influence cardiovascular disease risk.

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The role of linoleic acid in asthma and inflammatory markers: a Mendelian randomization study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqz130 ◽

2019 ◽

Vol 110 (3) ◽

pp. 685-690 ◽

Cited By ~ 2

Author(s):

Jie V Zhao ◽

C Mary Schooling

Keyword(s):

Linoleic Acid ◽

Blood Cell ◽

White Blood Cell ◽

Genetic Variants ◽

Mendelian Randomization ◽

European Ancestry ◽

Uk Biobank ◽

Reverse Causality ◽

The Uk

ABSTRACT Background Asthma is a common respiratory disease, possibly caused by autoimmunity. Linoleic acid (LA), the main n–6 (ω-6) PUFA from widely used vegetable oils, is thought to suppress immune responses that might have benefits for asthma. However, this question has not been examined in randomized controlled trials. Objectives To obtain unconfounded estimates, we assessed how genetically predicted LA affected asthma using 2-sample Mendelian randomization. We also examined its role in white blood cell traits (eosinophil, neutrophil, and low monocyte counts) identified as potential causal factors in asthma. Methods We used 18 uncorrelated, genome-wide significant genetic variants to predict LA, which we applied to a large genetic case (n = 19,954)–control (n = 107,715) study of asthma, to the UK Biobank (408,961 people of European ancestry with 26,332 asthma cases), and for white blood cell traits to the UK Biobank. We also repeated the analysis on asthma using 29 replicated, functionally relevant genetic variants. In addition, we examined the role of asthma in LA to assess reverse causality. Results Genetically predicted LA was associated with lower risk of asthma (OR: 0.89 per SD increase in LA; 95% CI: 0.85, 0.93), with no association of asthma with LA. Genetically predicted LA was associated with lower eosinophil count (−0.03; 95% CI: −0.061, −0.004) and lower neutrophil count (−0.04; 95% CI: −0.057, −0.023). These estimates were robust to different selections of genetic variants and sensitivity analyses. Conclusions LA might protect against asthma possibly via white blood cell traits, with relevance to the identification of effective new interventions for asthma.

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Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02494-4 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Maria Bruzelius ◽

Susanna C. Larsson

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Increased Risk ◽

Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

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Abstract P147: Genome Wide Assessment of Shared Genetic Architecture Between Rheumatoid Arthritis and Cardiovascular Diseases Using the UK Biobank Data

Circulation ◽

10.1161/circ.141.suppl_1.p147 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Yanjun Guo ◽

Wonil Chung ◽

Zhilei Shan ◽

Liming Liang

Keyword(s):

Cardiovascular Diseases ◽

Genetic Correlation ◽

Multiple Testing ◽

Mendelian Randomization ◽

Meta Analysis ◽

Uk Biobank ◽

Increased Risk ◽

The Uk ◽

Cardiovascular Traits ◽

Shared Genetic

Background: Patients with RA have a 2-10 folds increased risk of cardiovascular diseases (CVD) and CVD accounts for almost 50% of the excess mortality in patients with RA when compared with general population, but the mechanisms underlying such associations are largely unknown. Methods: We examined the genetic correlation, causality, and shared genetic variants between RA (Ncase=6,756, Ncontrol=452,476) and CVD (Ncase=44,246, Ncontrol=414,986) using LD Score regression (LDSC), generalized summary-data-based Mendelian Randomization (GSMR), and cross-trait meta-analysis in the UK Biobank Data. Results: In the present study, RA was significantly genetically correlated with MI, angina, CHD, and CVD after correcting for multiple testing (Rg ranges from 0.40 to 0.43, P<0.05/5). Interestingly, when stratified by frequent usage of aspirin and paracetamol, we observed increased genetic correlation between RA and CVD for participants without aspirin usage ( Rg increased to 0.54 [95%CI: 0.54, 0.78] for angina; P value=6.69х10 -6 ), and for participants with usage of paracetamol ( Rg increased to 0.75 [95%CI: 0.20, 1.29] for MI; P value=8.90х10 -3 ). Cross-trait meta-analysis identified 9 independent loci that were shared between RA and at least one of the genetically correlated CVD traits including PTPN22 at chr1p13.2 , BCL2L11 at chr2q13 , and CCR3 at chr3p21.31 ( P single trait <1х10 -3 and P meta <5х10 -8 ) highlighting potential shared etiology between them which include accelerating atherosclerosis and upregulating oxidative stress and vascular permeability. Finally, Mendelian randomization analyses observed inconsistent instrumental effects and were unable to conclude the causality and directionality between RA and CVD. Conclusion: Our results supported positive genetic correlation between RA and multiple cardiovascular traits, and frequent usage of aspirin and paracetamol may modify their associations, but instrumental analyses were unable to conclude the causality and directionality between them.

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Altered Cortical Brain Structure and Increased Risk for Disease Seen Decades After Perinatal Exposure to Maternal Smoking: A Study of 9000 Adults in the UK Biobank

Cerebral Cortex ◽

10.1093/cercor/bhz060 ◽

2019 ◽

Vol 29 (12) ◽

pp. 5217-5233 ◽

Cited By ~ 4

Author(s):

Lauren E Salminen ◽

Rand R Wilcox ◽

Alyssa H Zhu ◽

Brandalyn C Riedel ◽

Christopher R K Ching ◽

...

Keyword(s):

Brain Structure ◽

Brain Mri ◽

Population Based ◽

Smoke Exposure ◽

Sensitivity Analyses ◽

Uk Biobank ◽

Increased Risk ◽

Increase Risk ◽

Sensory Cortices ◽

The Uk

Abstract Secondhand smoke exposure is a major public health risk that is especially harmful to the developing brain, but it is unclear if early exposure affects brain structure during middle age and older adulthood. Here we analyzed brain MRI data from the UK Biobank in a population-based sample of individuals (ages 44–80) who were exposed (n = 2510) or unexposed (n = 6079) to smoking around birth. We used robust statistical models, including quantile regressions, to test the effect of perinatal smoke exposure (PSE) on cortical surface area (SA), thickness, and subcortical volumes. We hypothesized that PSE would be associated with cortical disruption in primary sensory areas compared to unexposed (PSE−) adults. After adjusting for multiple comparisons, SA was significantly lower in the pericalcarine (PCAL), inferior parietal (IPL), and regions of the temporal and frontal cortex of PSE+ adults; these abnormalities were associated with increased risk for several diseases, including circulatory and endocrine conditions. Sensitivity analyses conducted in a hold-out group of healthy participants (exposed, n = 109, unexposed, n = 315) replicated the effect of PSE on SA in the PCAL and IPL. Collectively our results show a negative, long term effect of PSE on sensory cortices that may increase risk for disease later in life.

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Causal Effect of the Triglyceride-Glucose Index and the Joint Exposure of Higher Glucose and Triglyceride With Extensive Cardio-Cerebrovascular Metabolic Outcomes in the UK Biobank: A Mendelian Randomization Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.583473 ◽

2021 ◽

Vol 7 ◽

Author(s):

Shucheng Si ◽

Jiqing Li ◽

Yunxia Li ◽

Wenchao Li ◽

Xiaolu Chen ◽

...

Keyword(s):

Mendelian Randomization ◽

Causal Effect ◽

Heart Diseases ◽

Cerebrovascular Diseases ◽

European Ancestry ◽

Uk Biobank ◽

Tyg Index ◽

Metabolic Outcomes ◽

Meta Regression ◽

The Uk

Background: The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking.Methods: A comprehensive factorial Mendelian randomization (MR) was performed in the UK Biobank cohort involving 273,368 individuals with European ancestry to assess and quantify these effects. The factorial MR, MR-PRESSO, MR-Egger, meta-regression, sensitivity analysis, positive control, and external verification were utilized. Outcomes include major outcomes [overall CVD, ischemic heart diseases (IHD), and cerebrovascular diseases (CED)] and minor outcomes [angina pectoris (AP), acute myocardial infarction (AMI), chronic IHD (CIHD), heart failure (HF), hemorrhagic stroke (HS), and ischemic stroke (IS)].Results: The TyG index significantly increased the risk of overall CVD [OR (95% CI): 1.20 (1.14–1.25)], IHD [OR (95% CI): 1.22 (1.15–1.29)], CED [OR (95% CI): 1.14 (1.05–1.23)], AP [OR (95% CI): 1.29 (1.20–1.39)], AMI [OR (95% CI): 1.27 (1.16–1.39)], CIHD [OR (95% CI): 1.21 (1.13–1.29)], and IS [OR (95% CI): 1.22 (1.06–1.40)]. Joint exposure to genetically higher GLU and TG was significantly associated with a higher risk of overall CVD [OR (95% CI): 1.17 (1.12–1.23)] and IHD [OR (95% CI): 1.22 (1.16–1.29)], but not with CED. The effect of GLU and TG was independent of each other genetically and presented dose–response effects in bivariate meta-regression analysis.Conclusions: Lifelong genetic exposure to higher GLU and TG was jointly associated with higher cardiac metabolic risk while the TyG index additionally associated with several cerebrovascular diseases. The TyG index could serve as a more sensitive pre-diagnostic indicator for CVD while the joint GLU and TG could offer a quantitative risk for cardiac metabolic outcomes.

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Abstract P633: Polygenic Susceptibility to Hypertension is Associated With Uncontrolled and Resistant Hypertension in Stroke Survivors

Stroke ◽

10.1161/str.52.suppl_1.p633 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Julian N Acosta ◽

Cameron Both ◽

Natalia Szejko ◽

Stacy Brown ◽

Nils H Petersen ◽

...

Keyword(s):

Resistant Hypertension ◽

Antihypertensive Drugs ◽

European Ancestry ◽

Risk Scores ◽

Uncontrolled Hypertension ◽

Stroke Survivors ◽

Cerebrovascular Event ◽

Uk Biobank ◽

Increased Risk ◽

The Uk

Introduction: Blood pressure (BP) is a highly heritable trait with numerous related genetic risk variants identified. While prior studies showed that polygenic susceptibility to hypertension (PSH) is associated with elevated BP, uncontrolled hypertension (UHTN), resistant hypertension (RHTN), and risk of stroke, its role after a cerebrovascular event remains unknown. We tested the hypothesis that PSH leads to higher BP and increased risk of UHTN and RHTN in stroke survivors. Methods: We conducted a nested study within the UK Biobank, including individuals of European ancestry with a prevalent ischemic or hemorrhagic stroke. To model PSH, we created polygenic risk scores (PRS) for systolic, diastolic, and pulse BP using 732 previously discovered loci. We divided the PRS into quintiles and used linear and logistic regression to test whether higher PSH led to higher observed BP as well as increased risk of UHTN (SBP >140 mmHg or DBP >90 mmHg) and RHTN (UHTN despite being on >=3 antihypertensive drugs) in stroke survivors. Results: Of the 502,536 participants enrolled in the UK Biobank, 5,815 (1.2%) with a prevalent stroke at enrollment were included. We found the following results across quintiles 1 through 5 of the systolic BP-based PRS: mean systolic BP 138.4, 140.6, 141.8, 142.9 and 145.8 mmHg (unadjusted p<0.0001, Figure’s left panel); risk of UHTN 46%, 51%, 52%, 56% and 59% (unadjusted p<0.0001, Figure’s center panel); and risk of RHTN 1.9%, 3.8%, 4.7%, 5.8% and 6.7% (unadjusted p<0.0001, Figure’s right panel). We obtained similar results when both evaluating diastolic and pulse BP-based PRSs and using adjusted multivariable models (all p<0.0001). Conclusion: PSH is associated with observed BP and the risk of UHTN and RHTN in stroke survivors. Follow up research should evaluate whether precision medicine strategies based on BP-related genetic information can help identify patients that could benefit from aggressive diagnostic and/or therapeutic interventions.

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Association of blood group and red blood cell transfusion with the incidence of antepartum, peripartum and postpartum venous thromboembolism

Scientific Reports ◽

10.1038/s41598-019-49566-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Chen Wang ◽

Isabelle Le Ray ◽

Brian Lee ◽

Agneta Wikman ◽

Marie Reilly

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Blood Cell ◽

Blood Group ◽

Red Blood Cell ◽

Blood Type ◽

Odds Ratios ◽

Increased Risk ◽

Abo Blood Type ◽

Rbc Transfusion

Abstract The increased risk of venous thromboembolism (VTE) associated with pregnancy is well-known and prophylaxis guidelines consider a number of risk factors. Although non-O blood group and red blood cell (RBC) transfusion are known to be associated with VTE risk, their contribution to pregnancy-associated VTE has received little attention. This study was conducted in a population-based cohort of 1,000,997 deliveries to women with no prior history of VTE or thrombophilia. The independent contributions of ABO blood type and RBC transfusion to the risks of antepartum, peripartum and postpartum VTE are reported as odds ratios adjusted for risk factors that are considered in current prophylaxis guidelines and other potential confounders. Compared with type O, A and B blood types have higher risk of antepartum and postpartum VTE, with odds ratios between 1.4 and 1.8. Transfusion around delivery has the largest increased risks and a dose-response effect, with adjusted odds ratios from 2.60 (1.71–3.97) for 1–2 units to 3.55 (1.32–9.55) for more than 5 units. ABO blood type and RBC transfusion were found to be independent risk factors for pregnancy-associated VTE. Further research is required to understand the underlying mechanisms and to conduct a risk-benefit assessment of the small volumes of RBCs transfused around delivery.

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Childhood obesity and multiple sclerosis: A Mendelian randomization study

Multiple Sclerosis Journal ◽

10.1177/13524585211001781 ◽

2021 ◽

pp. 135245852110017

Author(s):

Adil Harroud ◽

Ruth E Mitchell ◽

Tom G Richardson ◽

John A Morris ◽

Vincenzo Forgetta ◽

...

Keyword(s):

Multiple Sclerosis ◽

Childhood Obesity ◽

Mendelian Randomization ◽

Pubertal Timing ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Increased Risk ◽

Age At Puberty

Background: Higher childhood body mass index (BMI) has been associated with an increased risk of multiple sclerosis (MS). Objective: To evaluate whether childhood BMI has a causal influence on MS, and whether this putative effect is independent from early adult obesity and pubertal timing. Methods: We performed Mendelian randomization (MR) using summary genetic data on 14,802 MS cases and 26,703 controls. Large-scale genome-wide association studies provided estimates for BMI in childhood ( n = 47,541) and adulthood ( n = 322,154). In multivariable MR, we examined the direct effects of each timepoint and further adjusted for age at puberty. Findings were replicated using the UK Biobank ( n = 453,169). Results: Higher genetically predicted childhood BMI was associated with increased odds of MS (odds ratio (OR) = 1.26/SD BMI increase, 95% confidence interval (CI): 1.07–1.50). However, there was little evidence of a direct effect after adjusting for adult BMI (OR = 1.03, 95% CI: 0.70–1.53). Conversely, the effect of adult BMI persisted independent of childhood BMI (OR = 1.43; 95% CI: 1.01–2.03). The addition of age at puberty did not alter the findings. UK Biobank analyses showed consistent results. Sensitivity analyses provided no evidence of pleiotropy. Conclusion: Genetic evidence supports an association between childhood obesity and MS susceptibility, mediated by persistence of obesity into early adulthood but independent of pubertal timing.

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Birth weight, BMI in adulthood and latent autoimmune diabetes in adults: A Mendelian randomization study

10.1101/2021.10.25.21265464 ◽

2021 ◽

Author(s):

Yuxia Wei ◽

Yiqiang Zhan ◽

Josefin E. Lofvenborg ◽

Tiinamaija Tuomi ◽

Sofia Carlsson

Keyword(s):

Type 2 Diabetes ◽

Birth Weight ◽

Low Birth Weight ◽

Mendelian Randomization ◽

Autoimmune Diabetes ◽

Sensitivity Analyses ◽

Uk Biobank ◽

Latent Autoimmune Diabetes ◽

The Uk

Aims: Observational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birth weight and adult overweight/obesity. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomization (MR) design. In addition, we wanted to compare results for LADA and type 2 diabetes. Methods: We identified 129 SNPs as instrumental variables (IVs) for birth weight from a genome-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2,634 cases and 5,947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. Results: Genetically determined birth weight was inversely associated with LADA (OR per SD [~500 g] decrease in birth weight: 2.02, 95% CI: 1.37-2.97). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [~4.8 kg/m2] increase in BMI: 1.40, 95% CI: 1.14-1.71). Results persisted in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birth weight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. Conclusions/ interpretation: This study provides genetic support for a causal link between low birth weight, adult overweight/obesity, and LADA.

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