Causal Effect Of Body Mass Index Research Articles

Causal effects of BMI, waist circumference, and body fat percentage on the risk of bladder cancer: A Mendelian randomization study.

The causal role of body mass index (BMI) in bladder cancer (BC) by Mendelian randomization (MR) has not yet been reported. We evaluated the causal associations between the measures of obesity (BMI, waist circumference, and body fat percentage) and BC. We conducted a 2-sample MR analysis to assess the genetic effect of measures of obesity on BC. The BMI dataset (GWAS ID: ukb-b-2303) comprised 454,884 Europeans, and we identified 9,851,867 single nucleotide polymorphisms (SNPs). The waist circumference data (GWAS ID: ukb-b-9405) included 462,166 Europeans and 9,851,867 SNPs. The body fat percentage dataset (GWAS ID: ukb-a-264) contained data from 331,117 Europeans and 10,894,596 SNPs. For the outcome data, the GWAS ID was finn-b-C3_BLADDER, consisting of 1115 cases and 217,677 controls, with 16,380,466 SNPs. The inverse-variance weighted (IVW) model was used as the primary MR analysis. Cochran Q-statistic was used to identify heterogeneity between the SNPs. The MR-Egger and MR-PRESSO methods were employed to assess directional pleiotropy and outlier SNPs. We detected a decisive causal link between BMI and BC by the IVW analysis (odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.08-1.85, P = .011). The IVW analyses revealed a significant correlation between BC and waist circumference (OR = 1.55, 95% CI: 1.08-2.12, P = .016). However, the IVW method (OR = 1.49, 95% CI: 0.99-2.00, P = .05) did not report any statistical significance between body fat percentage and BC. We did not observe heterogeneity and directional pleiotropy in the 3 pairs of MR studies. The 2-sample MR analysis revealed a conceivable causal association between obesity (BMI, waist circumference) and BC.

Evaluating the effect of body mass index and 25-hydroxy-vitamin D level on basal cell carcinoma using Mendelian randomization

Basal cell carcinoma (BCC) is the most common cancer with a rising incidence among white-skinned individuals. A number of epidemiological studies have suggested that obesity and serum 25-hydroxy-vitamin D (25(OH)D) levels may affect the arising of BCC. To address this, we selected 443 and 96 single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and serum level of 25(OH)D from large-scale genome-wide association studies (GWAS), respectively. The univariable and multivariable two-sample Mendelian randomization (MR) analyses were conducted with a series of sensitivity analyses to ensure the results were reliable and reproducible. The results of univariable two-sample MR analysis showed that higher BMI was related to lower risk for BCC (Odds ratio(OR) = 0.90; 95% confidence interval (CI),[0.81,0.99]; p = 0.02). In addition, this causal effect of BMI on BCC still remained (OR = 0.88; 95%CI,[− 0.22, − 0.03], p-value = 0.008) after adjusting for 25(OH)D level in the multivariable MR analysis. However, the results suggested that 25(OH)D level was not associated with BCC(OR = 1.02; 95%CI, [0.94,1.09], p-value = 0.67). In conclusion, similar to the conclusions of retrospective observational studies, the MR results indicate that high BMI is an independent protective factor for BCC. Meanwhile, vitamin D levels may not be causally associated with the risk of basal cell carcinoma and increasing vitamin D supplementation is unlikely to reduce the risk.

Multisite chronic pain as a causal risk factor for coronary artery disease: findings from Mendelian randomization.

The potential consequences of the number of chronic pain sites (referred to multisite chronic pain) on the risk of cardiovascular diseases (CVDs) remain unclear. We attempted to investigate the causality of multisite chronic pain with CVDs and its possible causal mediators. Using summary genome-wide association statistics, two-sample Mendelian randomization (MR) analyses were performed to assess whether multisite chronic pain has a causal effect on the 3 CVDs including coronary artery disease, atrial fibrillation, and stroke. We then conducted MR mediation analyses to establish whether body mass index (BMI), smoking, and depression causally mediate any association. Genetic liability to multisite chronic pain was associated with increased risk of coronary artery disease (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.19-1.95 per one increase in the number of pain locations) but not with atrial fibrillation or stroke. We also found positive causal effects of multisite chronic pain on BMI, smoking, and depression and causal effects of BMI, smoking, and depression on coronary artery disease. In multivariable MR analyses, the excess risk of coronary artery disease was attenuated after adjusting for BMI (OR 1.43, 95% CI 1.05-1.93), smoking (OR 1.49, 95% CI 1.11-2.00), depression (OR 1.44, 95% CI 1.03-2.01), and 3 risk factors combined (OR 1.34, 95% CI 0.88-2.05). Our findings demonstrated that multisite chronic pain led to higher risk of coronary artery disease, which is partly mediated through BMI, smoking, and depression.

Causality of abdominal obesity on cognition: a trans-ethnic Mendelian randomization study.

Obesity has been associated with cognition in observational studies; however, whether its effect is confounding or a reverse causality remains inconclusive. This study aimed to investigate the causal relationships of overall obesity, measured by body mass index (BMI), and abdominal adiposity, measured by waist-hip ratio adjusted for BMI (WHRadjBMI), and cognition across European and Asian populations using Mendelian randomization (MR) analysis. We used publicly available genome-wide association study (GWAS) summary data of European ancestry, including BMI (n = 322,154) and WHRadjBMI (n = 210,088) from the GIANT consortium, and cognition performance (n = 257,828) from the UK Biobank and COGENT consortium. Data for individuals of Asian ancestry were retrieved from Taiwan Biobank to perform GWAS for BMI (n = 65,689), WHRadjBMI (n = 65,683), and Mini-Mental State Examination (MMSE, n = 21,273). MR analysis was carried out using the inverse-variance weighted method for the main results. Further, we examined the overall pleiotropy by MR-Egger intercept, and detected and adjusted for possible outliers using MR PRESSO. No causal effect of BMI on cognition performance (beta [95% CI] = 0.00 [-0.07, 0.07], p value = 0.91) was found for Europeans; however, a 1-SD increase in WHRadjBMI was associated with a 0.07 standardized score decrease in cognition performance (beta [95% CI] = -0.07 [-0.12, -0.02], p value = 0.006). Further, no causal effect of BMI on MMSE (beta [95% CI] = 0.01 [-0.08, 0.10], p = 0.91) was found for Asians; however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized score decrease in MMSE (beta [95% CI] = -0.17 [-0.30, -0.03], p = 0.02). In both populations, overall pleiotropy was not detected, and outliers did not affect the robustness of the main findings. This trans-ethnic MR study reveals that abdominal adiposity, as measured by WHR adjusted for BMI, impairs cognition, whereas weak evidence suggests that BMI impairs cognition.

Body Mass Index and Risk of Diabetic Nephropathy: A Mendelian Randomization Study.

The associations of obesity and diabetic nephropathy (DN) in type 2 diabetes are inconsistent in observational studies, and causality remains unclear. To explore the causal effect of body mass index (BMI) on DN, estimated glomerular filtration rate (eGFR), and proteinuria in type 2 diabetes by a 2-sample Mendelian randomization (MR) analysis. A total of 56 genetic variants were selected as instrumental variables for BMI in 158 284 participants from BioBank Japan, and their effects on DN risk, eGFR, and proteinuria were estimated in 3972 individuals with type 2 diabetes. Then, sex-stratified MR analysis was performed between BMI and DN. We selected generalized summary MR analysis as the primary method and 6 other robust methods to test MR assumptions. One SD increase in BMI was causally associated with higher DN risk [odds ratio (OR) 3.76, 95% CI 1.88-7.53, P < 0.001] and lower eGFR level (OR 0.71, 95% CI 0.59-0.86, P < 0.001). However, BMI was not causally associated with proteinuria (P = 0.22). Sex-stratified analyses indicated the causal effect of BMI on DN was stronger in women (OR 14.81, 95% CI 2.67-82.05, P = 0.002) than in men (OR 3.48, 95% CI 1.18-10.27, P = 0.02). Sensitivity analyses did not show evidence for violation of the MR assumptions. Genetic evidence showed that higher BMI levels were causally associated with increased risk of DN and decreased eGFR levels. Moreover, the increase in BMI level had a greater impact on DN risk in women.

Obesity, Type 2 Diabetes, and the Risk of Carpal Tunnel Syndrome: A Two-Sample Mendelian Randomization Study.

Some previous observational studies have reported an increased risk of carpal tunnel syndrome (CTS) in patients with obesity or type 2 diabetes (T2D), which was however, not observed in some other studies. In this study we performed a two-sample Mendelian randomization to assess the causal effect of obesity, T2D on the risk of CTS. Single nucleotide polymorphisms associated with the body mass index (BMI) and T2D were extracted from genome-wide association studies. Summary-level results of CTS were available through FinnGen repository. Univariable Mendelian randomization (MR) with inverse-variance-weighted method indicated a positive correlation of BMI with CTS risk [odds ratio (OR) 1.66, 95% confidence interval (CI), 1.39–1.97]. Genetically proxied T2D also significantly increased the risk of CTS [OR 1.17, 95% CI (1.07–1.29)]. The causal effect of BMI and T2D on CTS remained consistent after adjusting for each other with multivariable MR. Our mediation analysis indicated that 34.4% of BMI’s effect of CTS was mediated by T2D. We also assessed the effects of several BMI and glycemic related traits on CTS. Waist circumference and arm fat-free mass were also causally associated with CTS. However, the associations disappeared after adjusting for the effect of BMI. Our findings indicate that obesity and T2D are independent risk factors of CTS.

Effects of increased body mass index on employment status: a Mendelian randomisation study

BackgroundThe obesity epidemic may have substantial implications for the global workforce, including causal effects on employment, but clear evidence is lacking. Obesity may prevent people from being in paid work through poor health or through social discrimination. We studied genetic variants robustly associated with body mass index (BMI) to investigate its causal effects on employment.Dataset/methodsWhite UK ethnicity participants of working age (men 40–64 years, women 40–59 years), with suitable genetic data were selected in the UK Biobank study (N = 230,791). Employment status was categorised in two ways: first, contrasting being in paid employment with any other status; and second, contrasting being in paid employment with sickness/disability, unemployment, early retirement and caring for home/family. Socioeconomic indicators also investigated were hours worked, household income, educational attainment and Townsend deprivation index (TDI). We conducted observational and two-sample Mendelian randomisation (MR) analyses to investigate the effect of increased BMI on employment-related outcomes.ResultsRegressions showed BMI associated with all the employment-related outcomes investigated. MR analyses provided evidence for higher BMI causing increased risk of sickness/disability (OR 1.08, 95% CI 1.04, 1.11, per 1 Kg/m2 BMI increase) and decreased caring for home/family (OR 0.96, 95% CI 0.93, 0.99), higher TDI (Beta 0.038, 95% CI 0.018, 0.059), and lower household income (OR 0.98, 95% CI 0.96, 0.99). In contrast, MR provided evidence for no causal effect of BMI on unemployment, early retirement, non-employment, hours worked or educational attainment. There was little evidence for causal effects differing by sex or age. Robustness tests yielded consistent results.DiscussionBMI appears to exert a causal effect on employment status, largely by affecting an individual’s health rather than through increased unemployment arising from social discrimination. The obesity epidemic may be contributing to increased worklessness and therefore could impose a substantial societal burden.

Causal Effects of Body Mass Index on Airflow Obstruction and Forced Mid-Expiratory Flow: A Mendelian Randomization Study Taking Interactions and Age-Specific Instruments Into Consideration Toward a Life Course Perspective.

Obesity has complex links to respiratory health. Mendelian randomization (MR) enables assessment of causality of body mass index (BMI) effects on airflow obstruction and mid-expiratory flow. In the adult SAPALDIA cohort, recruiting 9,651 population-representative samples aged 18–60 years at baseline (female 51%), BMI and the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) as well as forced mid-expiratory flow (FEF25–75%) were measured three times over 20 follow-up years. The causal effects of BMI in childhood and adulthood on FEV1/FVC and FEF25–75% were assessed in predictive (BMI averaged over 1st and 2nd, lung function (LF) averaged over 2nd and 3rd follow-up; N = 2,850) and long-term cross-sectional models (BMI and LF averaged over all follow-ups; N = 2,728) by Mendelian Randomization analyses with the use of weighted BMI allele score as an instrument variable and two-stage least squares (2SLS) method. Three different BMI allele scores were applied to specifically capture the part of BMI in adulthood that likely reflects tracking of genetically determined BMI in childhood. The main causal effects were derived from models containing BMI (instrumented by BMI genetic score), age, sex, height, and packyears smoked as covariates. BMI interactions were instrumented by the product of the instrument (BMI genetic score) and the relevant concomitant variable. Causal effects of BMI on FEV1/FVC and FEF25–75% were observed in both the predictive and long-term cross-sectional models. The causal BMI- LF effects were negative and attenuated with increasing age, and stronger if instrumented by gene scores associated with childhood BMI. This non-standard MR approach interrogating causal effects of multiplicative interaction suggests that the genetically rooted part of BMI patterns in childhood may be of particular relevance for the level of small airway function and airflow obstruction later in life. The methodological relevance of the results is first to point to the importance of a life course perspective in studies on the etiological role of BMI in respiratory health, and second to point out novel methodological aspects to be considered in future MR studies on the causal effects of obesity related phenotypes.

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

Studies 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.

Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study

BackgroundLow lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation.MethodsWe used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV1, FVC, and FEV1/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2.ResultsIn step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs.ConclusionsTo our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI.

Assessment of a causal relationship between body mass index and atopic dermatitis

Assessment of a causal relationship between body mass index and atopic dermatitis

Body Shape and Alzheimer's Disease: A Mendelian Randomization Analysis.

Obesity has been reported to be related to memory impairment and decline in cognitive function, possibly further leading to the development of Alzheimer’s disease (AD). However, observational studies revealed both negative and positive associations between body shape (BS) and AD, thereby making it difficult to confirm causality due to residual confounds and reverse causation. Thus, using genome-wide association study summary data, two-sample Mendelian randomization (MR) analyses were applied to identify whether there exists a causal association between BS and AD. BS was measured using anthropometric traits (ATs) in this study, including body mass index (BMI), waist-to-hip ratio (WHR), waist-to-hip ratio adjusted by body mass index (WHRadjBMI), and waist circumference (WC). The associations of single nucleotide polymorphisms (SNP) with each AT and AD were obtained separately from aggregated data from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and International Genomics of Alzheimer’s Project (IGAP) summary data (17,008 cases with AD and 37,154 controls). An inverse-variance weighted method was applied to obtain the overall causal estimate for multiple instrumental SNPs. The odds ratio (OR) [95% confidence interval (CI)] for AD risk per 1-SD difference in BMI was 1.04 (0.88, 1.23), in WHR was 1.01 (0.77, 1.33), in WHRadjBMI was 1.12 (0.89, 1.41), and in WC was 1.02 (0.82, 1.27). Furthermore, simulation analyses of survivor bias indicated the overall causal effect of BMI on risk of AD was not biased. In conclusion, the evidence from MR analyses showed no casual effect of BS on AD risk, which is inconsistent with the results from previous observational studies. The biological mechanism underlying the findings warrants further study.

Association Between Premorbid Body Mass Index and Amyotrophic Lateral Sclerosis: Causal Inference Through Genetic Approaches.

Purpose: Inverse association between premorbid body mass index (BMI) and amyotrophic lateral sclerosis (ALS) was implied in observational studies; however, whether this association is causal remains largely unknown.Materials and Methods: We first conducted a meta-analysis to investigate whether there exits an association between premorbid BMI and ALS. We then employed a two-sample Mendelian randomization approach to evaluate the causal relationship of genetically increased BMI with the risk of ALS. The Mendelian randomization analysis was implemented using summary statistics for independent instruments obtained from large-scale genome-wide association studies of BMI (up to ~770,000 individuals) and ALS (up to ~81,000 individuals). The causal effect of BMI on ALS was estimated using inverse-variance weighted methods and was further validated through extensive complementary and sensitivity analyses.Results: The meta-analysis showed that a unit increase of premorbid BMI can result in about 3.0% (95% CI 2.1–4.5%) risk reduction of ALS. Using 1,031 instruments that were strongly related to BMI, the causal effect of per one standard deviation increase of BMI was estimated to be 1.04 (95% CI 0.97–1.11, p = 0.275) in the European population. This null association between BMI and ALS also held in the East Asian population and was robust against various modeling assumptions and outlier biases. Additionally, the Egger-regression and MR-PRESSO ruled out the possibility of horizontal pleiotropic effects of instruments.Conclusion: Our results do not support the causal role of genetically increased or decreased BMI on the risk of ALS.

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

Given 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. We performed Mendelian randomization (MR) analyses of the effects of BMI on smoking behaviour in UK Biobank and the Tobacco and Genetics Consortium genome-wide association study (GWAS), on cotinine levels and nicotine metabolite ratio (NMR) in published GWAS and on DNA methylation in the Avon Longitudinal Study of Parents and Children. Our results indicate that higher BMI causally influences lifetime smoking, smoking initiation, smoking heaviness and also DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus, but we do not see evidence for an effect on smoking cessation. While there is no strong evidence that BMI causally influences cotinine levels, suggestive evidence for a negative causal influence on NMR may explain this. There is a causal effect of BMI on smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism.

The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.