scholarly journals Body mass index and mortality in UK Biobank: revised estimates using Mendelian randomization

2018 ◽  
Author(s):  
Kaitlin H Wade ◽  
David Carslake ◽  
Naveed Sattar ◽  
George Davey Smith ◽  
Nicholas J Timpson
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genotypic Variation ◽  
Lung Cancer Mortality ◽  
Causal Role ◽  
Uk Biobank ◽  
All Cause Mortality

AbstractObjectiveObtain estimates of the causal relationship between different levels of body mass index (BMI) and mortality.MethodsMendelian randomization (MR) was conducted using genotypic variation reliably associated with BMI to test the causal effect of increasing BMI on all-cause and cause-specific mortality in participants of White British ancestry in UK Biobank.ResultsMR analyses supported existing evidence for a causal association between higher levels of BMI and greater risk of all-cause mortality (hazard ratio (HR) per 1kg/m2: 1.02; 95% CI: 0.97,1.06) and mortality from cardiovascular diseases (HR: 1.12; 95% CI: 1.02, 1.23), specifically coronary heart disease (HR: 1.19; 95% CI: 1.05, 1.35) and those other than stroke/aortic aneurysm (HR: 1.13; 95% CI: 0.93, 1.38), stomach cancer (HR: 1.30; 95% CI: 0.91, 1.86) and oesophageal cancer (HR: 1.08; 95% CI: 0.84, 1.38), and with decreased risk of lung cancer mortality (HR: 0.97; 95% CI: 0.84, 1.11). Sex-stratified analyses supported a causal role of higher BMI in increasing the risk of mortality from bladder cancer in males and other causes in females, but in decreasing the risk of respiratory disease mortality in males. The characteristic J-shaped observational association between BMI and mortality was visible with MR analyses but with a smaller value of BMI at which mortality risk was lowest and apparently flatter over a larger range of BMI.ConclusionResults support a causal role of higher BMI in increasing the risk of all-cause mortality and mortality from other causes. However, studies with greater numbers of deaths are needed to confirm the current findings.

scholarly journals Assessing the causal role of body mass index on cardiovascular health in young adults: Mendelian randomization and recall-by-genotype analyses

2017 ◽  
Author(s):  
Kaitlin H. Wade ◽  
Scott T. Chiesa ◽  
Alun D. Hughes ◽  
Nish Chaturvedi ◽  
Marietta Charakida ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Young Adults ◽  
Body Mass ◽  
Cardiovascular Health ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Left Ventricular ◽  
Causal Role ◽  
A Genome

ABSTRACTBackgroundMendelian randomization (MR) studies of body mass index (BMI) and cardiovascular health in mid-to-late life suggest causal relationships, but the nature of these has not been explored systematically at younger ages. Using complementary MR and recall-by-genotype (RbG) methodologies, our objective was to estimate the causal effect of BMI on detailed measures of cardiovascular health in a population of young healthy adults.Methods and FindingsData from the Avon Longitudinal Study of Parents and Children were used. For MR analyses, a genetic risk score (GRS) comprising 97 independent single nucleotide polymorphisms (SNPs) and constructed using external weighting was used as an instrument to test the causal effect of each unit increase in BMI (kg/m2) on selected cardiovascular phenotypes measured at age 17 (N=7909). An independent enriched sample from the same cohort participated in a RbG study at age 21, which enabled more detailed cardiovascular phenotyping (N=418; 191/227 from the lower/upper ∼30% of a genome-wide GRS distribution predicting variation in BMI). The causal effect of BMI on the additional cardiovascular phenotypes was assessed by comparing the two recalled groups. Difference in mean BMI between RbG groups was 3.85kg/m2 (95% CI: 2.53, 4.63; P=6.09×1011). In both MR and RbG analyses, results indicated that higher BMI causes higher blood pressure (BP) and left ventricular mass (indexed to height2.7, LVMI) in young adults (e.g. difference in LVMI per kg/m2 using MR: 1.07g/m2.7; 95% CI: 0.62, 1.52; P=3.87×10−06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results indicated a causal role of higher BMI on higher stroke volume (SV; difference per 3.58kg/m2: 1.49ml/m2.04; 95% CI: 0.62, 2.35; P=0.001) and cardiac output (CO; difference per 3.58kg/m2: 0.11l /min/m1.83; 95% CI: 0.03, 0.19; P=0.01). Neither analysis supported a causal role of higher BMI on heart rate.ConclusionsComplementary MR and RbG causal methodologies, together with a range of appropriate sensitivity analyses, showed that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. These consistent results support efforts to prevent or reverse obesity in the young.

scholarly journals Assessing the causal impact of adiposity variation on rates of hospital admission: Application of Mendelian randomization

2020 ◽  
Author(s):  
Audinga-Dea Hazewinkel ◽  
Padraig Dixon ◽  
Rebecca Richmond ◽  
Kaitlin H Wade
Keyword(s):  
Body Mass Index ◽  
Hospital Admission ◽  
Body Mass ◽  
Hospital Admissions ◽  
Mendelian Randomization ◽  
Causal Role ◽  
Hospital Admission Rate ◽  
Admission Rates ◽  
Waist Hip Ratio

Background Body mass index (BMI) and waist-hip-ratio (WHR) are measures of adiposity, the former being a good marker for overall total body fat, the latter describing regional adiposity. Higher adiposity has been associated with the increased prevalence of many chronic diseases and a positive association between BMI and increased hospital admissions has previously been established. The aim of this study was to estimate the causal relationship between BMI, WHR and WHR adjusted for BMI (WHRadjBMI) and yearly hospital admission rates. Methods and Findings Mendelian randomization (MR) approaches were used to test the causal effect of BMI, WHR and WHRadjBMI on yearly hospital admission rates. Using data on 310,471 participants of White-British ancestry from the UK Biobank, we performed one-sample and two-sample MR analyses on the exposures individually and in a multivariable setting. MR analyses supported a causal role of adiposity on hospital admissions, with consistency across one- and two-sample MR methods. Primarily, one-sample MR analyses estimated fold-increases in yearly hospital admission rates of 1.13 (95% CI: 1.02, 1.27), 1.26 (95% CI: 1.00, 1.58) and 1.22 (95% CI: 1.01, 1.47) per SD for BMI, WHR and WHRadjBMI, respectively. A multivariable approach yielded estimates of 1.04 (95% CI: 0.99, 1.03) for BMI and 1.31 (95% CI: 1.04, 1.67) for WHR, while adjusting for WHR and BMI, respectively. Conclusions The results support a causal role of higher BMI and WHR in increasing the yearly hospital admission rate. The attenuation of the BMI effect, when adjusting for WHR in the multivariable MR analyses, suggested that an adverse fat distribution, rather than a higher BMI itself, may drive the relationship between adiposity and increased risk of hospital admission. Keywords: Body mass index (BMI), waist-hip-ratio (WHR), hospital admission, Mendelian randomization

scholarly journals The effect of body mass index on smoking behaviour and nicotine metabolism: a Mendelian randomization study

2018 ◽  
Author(s):  
Amy E. Taylor ◽  
Rebecca C. Richmond ◽  
Teemu Palviainen ◽  
Anu Loukola ◽  
Jaakko Kaprio ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Dna Methylation ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Smoking Initiation ◽  
Smoking Behaviour ◽  
Bidirectional Association ◽  
Metabolite Ratio ◽  
Nicotine Metabolite Ratio

AbstractBackgroundGiven clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight.Methods and FindingsWe undertook Mendelian randomization analyses using 97 genetic variants associated with BMI. We performed two sample Mendelian randomization analyses of the effects of BMI on smoking behaviour in UK Biobank (N=335,921) and the Tobacco and Genetics consortium genomewide association study (GWAS) (N≤74,035) respectively, and two sample Mendelian randomization analyses of the effects of BMI on cotinine levels (N≤4,548) and nicotine metabolite ratio (N≤1,518) in published GWAS, and smoking-related DNA methylation in the Avon Longitudinal Study of Parents and Children (N≤846).In inverse variance weighted Mendelian randomization analysis, there was evidence that higher BMI was causally associated with smoking initiation (OR for ever vs never smoking per one SD increase in BMI: 1.19, 95% CI: 1.11 to 1.27) and smoking heaviness (1.45 additional cigarettes smoked per day per SD increase in BMI, 95% CI: 1.03 to 1.86), but little evidence for a causal effect with smoking cessation. Results were broadly similar using pleiotropy robust methods (MR-Egger, median and weighted mode regression). These results were supported by evidence for a causal effect of BMI on DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus. There was no strong evidence that BMI was causally associated with cotinine, but suggestive evidence for a causal negative association with the nicotine metabolite ratio.ConclusionsThere is a causal bidirectional association between BMI and smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism. It may be useful to consider BMI and smoking together when designing prevention strategies to minimise the effects of these risk factors on health outcomes.

scholarly journals Application of Mendelian Randomization to Investigate the Association of Body Mass Index with Health Care Costs

2020 ◽  
Vol 40 (2) ◽  
pp. 156-169 ◽  
Author(s):  
Christoph F. Kurz ◽  
Michael Laxy
Keyword(s):  
Health Care ◽  
Body Mass Index ◽  
Body Mass ◽  
Health Care Costs ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Omitted Variables ◽  
Care Costs ◽  
Genetic Instruments

Causal effect estimates for the association of obesity with health care costs can be biased by reversed causation and omitted variables. In this study, we use genetic variants as instrumental variables to overcome these limitations, a method that is often called Mendelian randomization (MR). We describe the assumptions, available methods, and potential pitfalls of using genetic information and how to address them. We estimate the effect of body mass index (BMI) on total health care costs using data from a German observational study and from published large-scale data. In a meta-analysis of several MR approaches, we find that models using genetic instruments identify additional annual costs of €280 for a 1-unit increase in BMI. This is more than 3 times higher than estimates from linear regression without instrumental variables (€75). We found little evidence of a nonlinear relationship between BMI and health care costs. Our results suggest that the use of genetic instruments can be a powerful tool for estimating causal effects in health economic evaluation that might be superior to other types of instruments where there is a strong association with a modifiable risk factor.

scholarly journals Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study

PLoS Medicine ◽  
2019 ◽  
Vol 16 (12) ◽  
pp. e1002982 ◽  
Author(s):  
Michael Wainberg ◽  
Anubha Mahajan ◽  
Anshul Kundaje ◽  
Mark I. McCarthy ◽  
Erik Ingelsson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Uk Biobank ◽  
The Uk

scholarly journals Estimating the causal effect of body mass index on hay fever, asthma and lung function using Mendelian randomization

Allergy ◽  
2017 ◽  
Vol 73 (1) ◽  
pp. 153-164 ◽  
Author(s):  
T. Skaaby ◽  
A. E. Taylor ◽  
B. H. Thuesen ◽  
R. K. Jacobsen ◽  
N. Friedrich ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Lung Function ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Hay Fever

scholarly journals Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giorgio Pistis ◽  
Yuri Milaneschi ◽  
Caroline L. Vandeleur ◽  
Aurélie M. Lasserre ◽  
Brenda W.J.H. Penninx ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect ◽  
Fat Distribution ◽  
The Body ◽  
Causal Role ◽  
Depression Symptoms ◽  
Specific Symptom ◽  
Atypical Depression ◽  
Atypical Symptoms

AbstractStudies considering the causal role of body mass index (BMI) for the predisposition of major depressive disorder (MDD) based on a Mendelian Randomization (MR) approach have shown contradictory results. These inconsistent findings may be attributable to the heterogeneity of MDD; in fact, several studies have documented associations between BMI and mainly the atypical subtype of MDD. Using a MR approach, we investigated the potential causal role of obesity in both the atypical subtype and its five specific symptoms assessed according to the Statistical Manual of Mental Disorders (DSM), in two large European cohorts, CoLaus|PsyCoLaus (n = 3350, 1461 cases and 1889 controls) and NESDA|NTR (n = 4139, 1182 cases and 2957 controls). We first tested general obesity measured by BMI and then the body fat distribution measured by waist-to-hip ratio (WHR). Results suggested that BMI is potentially causally related to the symptom increase in appetite, for which inverse variance weighted, simple median and weighted median MR regression estimated slopes were 0.68 (SE = 0.23, p = 0.004), 0.77 (SE = 0.37, p = 0.036), and 1.11 (SE = 0.39, p = 0.004). No causal effect of BMI or WHR was found on the risk of the atypical subtype or for any of the other atypical symptoms. Our findings show that higher obesity is likely causal for the specific symptom of increase in appetite in depressed participants and reiterate the need to study depression at the granular level of its symptoms to further elucidate potential causal relationships and gain additional insight into its biological underpinnings.

scholarly journals A phenome-wide multi-directional Mendelian randomization analysis of atrial fibrillation

2020 ◽  
Author(s):  
Qin Wang ◽  
Tom G Richardson ◽  
Eleanor Sanderson ◽  
Mika Ala-Korpela ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Body Mass Index ◽  
Coronary Artery ◽  
Mendelian Randomization ◽  
Causal Role ◽  
Coronary Artery Diseases ◽  
Genetic Liability

AbstractBackgroundThe prevalence of atrial fibrillation (AF) is increasing with an aging worldwide population, yet a comprehensive understanding of its causes and consequences remains limited.ObjectivesTo assess the causes and consequences of AF via a multi-directional Mendelian randomization (MR) analysis scanning thousands of traits in a hypothesis-free approach.MethodsWe used publicly available GWAS data centralised and harmonised by the IEU open GWAS database. We assessed the potential causal role of 5048 exposures on risk of AF and the causal role of genetic liability to AF on 10,308 outcomes via two-sample MR analysis. Multivariable MR analysis was further conducted to explore the comparative role of identified risk factors.ResultsMR analysis suggested that 55 out of 5048 exposure traits, including four proteins, play a causal role in AF (P < 1e-5 allowing for multiple comparisons). Multivariable analysis suggested that higher body mass index, height, systolic blood pressure as well as genetic liability to coronary artery diseases independently cause AF. Three out of the four proteins (DUSP13, TNFSF12 and IL6R) had a drug prioritising score for atrial fibrillation of 0.26, 0.38 and 0.88, respectively (values closer to 1 indicating stronger evidence of the protein as a potential drug target). Genetic liability to AF was linked to a higher risk of cardioembolic ischemic stroke.ConclusionsBody mass index, height, systolic blood pressure and genetic liability to coronary artery diseases are independent causal risk factors for AF. Several proteins including DUSP13, IL-6R and TNFSF12 may represent therapeutic potential for preventing AF.

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