SU46USING MENDELIAN RANDOMIZATION TO TEST CAUSAL BIDIRECTIONAL INFLUENCES BETWEEN PHYSICAL ACTIVITY AND DEPRESSION

Abstract Aims Observational evidence suggests that physical activity (PA) is inversely and sedentarism positively related with cardiovascular disease risk. We performed a two-sample Mendelian randomization (MR) analysis to examine whether genetically predicted PA and sedentary behavior are related to coronary artery disease, myocardial infarction, and ischemic stroke. Methods and results We used single nucleotide polymorphisms (SNPs) associated with self-reported moderate to vigorous PA (n = 17), accelerometer based PA (n = 7) and accelerometer fraction of accelerations > 425 milli-gravities (n = 7) as well as sedentary behavior (n = 6) in the UK Biobank as instrumental variables in a two sample MR approach to assess whether these exposures are related to coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D genome-wide association study (GWAS) or ischemic stroke in the MEGASTROKE GWAS. The study population included 42,096 cases of coronary artery disease (99,121 controls), 27,509 cases of myocardial infarction (99,121 controls), and 34,217 cases of ischemic stroke (404,630 controls). We found no associations between genetically predicted self-reported moderate to vigorous PA, accelerometer-based PA or accelerometer fraction of accelerations > 425 milli-gravities as well as sedentary behavior with coronary artery disease, myocardial infarction, and ischemic stroke. Conclusions These results do not support a causal relationship between PA and sedentary behavior with risk of coronary artery disease, myocardial infarction, and ischemic stroke. Hence, previous observational studies may have been biased. Graphic abstract

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Assessing the Causality Factors in the Association between (Abdominal) Obesity and Physical Activity among the Newfoundland Population–-A Mendelian Randomization Analysis

Genetics & Epigenetics ◽

10.4137/geg.s38289 ◽

2016 ◽

Vol 8 ◽

pp. GEG.S38289 ◽

Cited By ~ 2

Author(s):

Frank Barning ◽

Taraneh Abarin

Keyword(s):

Physical Activity ◽

Newfoundland And Labrador ◽

Mendelian Randomization ◽

Causal Effect ◽

Intervention Strategies ◽

Nucleotide Polymorphisms ◽

Fto Gene ◽

Single Nucleotide ◽

Similar Association ◽

Randomization Analysis

A total of 1,263 adults from Newfoundland and Labrador were studied in the research. Body mass index (BMI) and percent trunk fat (PTF) were analyzed as biomarkers for obesity. The Mendelian randomization (MR) approach with two single-nucleotide polymorphisms in the fat-mass and obesity (FTO) gene as instruments was employed to assess the causal effect. In both genders, increasing physical activity significantly reduced BMI and PTF when adjusted for age and the FTO gene. The effect of physical activity was stronger on PTF than BMI. Direct observational analyses showed significant increase in BMI/PTF when physical activity decreased. A similar association in MR analyses was not significant. The association between physical activity and BMI/PTF could be due to reversed causality or common confounding factors. Our study provides insights into the causal contributions of obesity to physical activity in adults. Health intervention strategies to increase physical activity among adults should include some other plans such as improving diet for reducing obesity.

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Association of Physical Activity with Body Composition: A Mendelian Randomization Study

10.31219/osf.io/e3mrx ◽

2021 ◽

Author(s):

Ferris Alaa Ramadan ◽

Katherine Ellingson ◽

Yann Klimentidis

Keyword(s):

Physical Activity ◽

Body Composition ◽

Sedentary Behavior ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Protective Effects ◽

Dietary Interventions ◽

The Uk

Background. Studies suggest that body composition can be improved through physical activity (PA) independently of dietary interventions. A separate line of evidence suggests that PA may reduce high-risk visceral adipose tissue (VAT), without clinically meaningful weight change. Genome-wide association studies have previously identified genetic markers associated with PA behaviors and may provide an opportunity to evaluate hypothesized causal relationships with body composition. Methods. We performed a Mendelian randomization (MR) study to test the incremental benefits of various PA exposures on body composition outcomes as assessed by anthropometric indices, lean body mass (LBM) (kg), body fat (%), and VAT (kg). Genetic instruments were identified for both self-reported and accelerometer-measured PA, including sedentary behavior. Outcomes included anthropometric and dual-energy X-ray absorptiometry measures of adiposity, extracted from the UK Biobank and the largest publicly available consortia. Multivariable MR (MVMR) included educational attainment as a covariate to address potential confounding. Sensitivity analyses were evaluated for weak instrument bias and pleiotropic effects.Results. We did not identify associations between genetically-predicted sedentary behavior (self-reported or accelerometer) and body composition outcomes in MVMR analyses. All analyses for self-reported moderate PA were null for body composition outcomes, including BMI, LBM and VAT. Genetically-predicted PA at higher intensities was protective against VAT in MR and MVMR analyses of both accelerometer-measured vigorous PA (MVMR β = -0.15, 95% Confidence Interval (CI): -0.24, -0.07, p<0.001) and self-reported participation in strenuous sports or other exercises (MVMR β = -0.27, 95%CI: -0.52, -0.01, p=0.034), and was robust across several sensitivity analyses. Conclusions. We did not identify evidence of a causal relationship between genetically-predicted PA and body composition, with the exception of a putatively protective effect of higher-intensity PA on VAT. Protective effects of PA against VAT may support prior evidence of biological pathways through which PA decreases risk of downstream cardiometabolic diseases.

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Genetically Determined Physical Activity and Its Association with Circulating Blood Cells

Genes ◽

10.3390/genes10110908 ◽

2019 ◽

Vol 10 (11) ◽

pp. 908 ◽

Cited By ~ 2

Author(s):

Femke M. Prins ◽

M. Abdullah Said ◽

Yordi J. van de Vegte ◽

Niek Verweij ◽

Hilde E. Groot ◽

...

Keyword(s):

Physical Activity ◽

Blood Cells ◽

Fixed Effects ◽

Mendelian Randomization ◽

P Value ◽

Nucleotide Polymorphisms ◽

Increased Risk ◽

Inflammatory State ◽

The Uk ◽

Genetically Determined

Lower levels of physical activity (PA) have been associated with increased risk of cardiovascular disease. Worldwide, there is a shift towards a lifestyle with less PA, posing a serious threat to public health. One of the suggested mechanisms behind the association between PA and disease development is through systemic inflammation, in which circulating blood cells play a pivotal role. In this study we investigated the relationship between genetically determined PA and circulating blood cells. We used 68 single nucleotide polymorphisms associated with objectively measured PA levels to perform a Mendelian randomization analysis on circulating blood cells in 222,645 participants of the UK Biobank. For inverse variance fixed effects Mendelian randomization analyses, p < 1.85 × 10−3 (Bonferroni-adjusted p-value of 0.05/27 tests) was considered statistically significant. Genetically determined increased PA was associated with decreased lymphocytes (β = –0.03, SE = 0.008, p = 1.35 × 10−3) and decreased eosinophils (β = –0.008, SE = 0.002, p = 1.36 × 10−3). Although further mechanistic studies are warranted, these findings suggest increased physical activity is associated with an improved inflammatory state with fewer lymphocytes and eosinophils.

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Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian-randomization study based on 79 148 prostate-cancer cases and 61 106 controls

International Journal of Epidemiology ◽

10.1093/ije/dyz235 ◽

2019 ◽

Vol 49 (2) ◽

pp. 587-596 ◽

Cited By ~ 5

Author(s):

Nabila Kazmi ◽

Philip Haycock ◽

Konstantinos Tsilidis ◽

Brigid M Lynch ◽

Therese Truong ◽

...

Keyword(s):

Physical Activity ◽

Prostate Cancer ◽

Risk Factors ◽

Cancer Risk ◽

Serum Iron ◽

Mendelian Randomization ◽

Prostate Cancer Risk ◽

Uk Biobank ◽

Monounsaturated Fat ◽

Aggressive Prostate Cancer

Abstract Background Prostate cancer is the second most common male cancer worldwide, but there is substantial geographical variation, suggesting a potential role for modifiable risk factors in prostate carcinogenesis. Methods We identified previously reported prostate cancer risk factors from the World Cancer Research Fund (WCRF)’s systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79 148 cases and 61 106 controls) or aggressive (15 167 cases and 58 308 controls) prostate cancer using Mendelian randomization (MR) based on genome-wide association-study summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7844 prostate-cancer cases and 204 001 controls). Results WCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms. For overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical activity, OR = 0.49 (0.33–0.72; P = 0.0003); serum iron, OR = 0.92 (0.86–0.98; P = 0.007); body mass index (BMI), OR = 0.90 (0.84–0.97; P = 0.003); and monounsaturated fat, OR = 1.11 (1.02–1.20; P = 0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive-prostate-cancer risk: OR = 1.07 (1.01–1.15; P = 0.03). Conclusions The results for physical activity, serum iron, BMI, monounsaturated fat and height are compatible with causality for prostate cancer. The results suggest that interventions aimed at increasing physical activity may reduce prostate-cancer risk, although interventions to change other risk factors may have negative consequences on other diseases.

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Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian randomization study based on 79,148 prostate cancer cases and 61,106 controls

10.1101/674820 ◽

2019 ◽

Author(s):

Nabila Kazmi ◽

Philip Haycock ◽

Konstantinos Tsilidis ◽

Brigid M. Lynch ◽

Therese Truong ◽

...

Keyword(s):

Physical Activity ◽

Prostate Cancer ◽

Risk Factors ◽

Cancer Research ◽

Cancer Risk ◽

Serum Iron ◽

Mendelian Randomization ◽

Prostate Cancer Risk ◽

Uk Biobank ◽

Unsaturated Fat

SummaryBackgroundProstate cancer is the second most common male cancer worldwide, but there is substantial geographical variation suggesting a potential role for modifiable risk factors in prostate carcinogenesis.MethodsWe identified previously reported prostate cancer risk factors from the World Cancer Research Fund’s (WCRF) systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79,148 cases and 61,106 controls) or aggressive (15,167 cases and 58,308 controls) prostate cancer using Mendelian randomization (MR) based on genome wide association study (GWAS) summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7,844 prostate cancer cases and 204,001 controls).FindingsWCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms (SNPs). In MR analyses for overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical-activity, OR=0.49 (0.33-0.72; p=0.0003); serum iron, OR=0.92 (0.86-0.98; p=0.007); body mass index (BMI), OR=0.90 (0.84-0.97; p=0.003); and mono-unsaturated fat, OR=1.11 (1.02-1.20; p=0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive prostate cancer risk: OR=1.07 (1.01-1.15; p=0.03).InterpretationThe results for physical-activity, serum iron, BMI, mono-unsaturated fat and height are compatible with causality for prostate cancer but more research is needed to rule out violations of MR assumptions for some risk factors. The results suggest that interventions aimed at increasing physical activity may reduce prostate cancer risk, but the direction of effects of BMI, and iron are at odds with their effects on other diseases, so the overall public health impact of intervening on these need to be considered.FundingWorld Cancer Research Fund International (2015/1421), Cancer Research UK program grant (C18281/A19169), National Institute for Health Research, Bristol Biomedical Research Centre, and Victorian Cancer Agency (MCRF18005).

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The causal relationships of device-measured physical activity with bipolar disorder and schizophrenia in adults: A 2-Sample mendelian randomization study

Journal of Affective Disorders ◽

10.1016/j.jad.2019.11.034 ◽

2020 ◽

Vol 263 ◽

pp. 598-604 ◽

Cited By ~ 1

Author(s):

Heli Sun ◽

Xue Gao ◽

Ximei Que ◽

Long Liu ◽

Jinsha Ma ◽

...

Keyword(s):

Physical Activity ◽

Bipolar Disorder ◽

Mendelian Randomization ◽

Causal Relationships

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Abstract P199: Alcohol Consumption Modified the Effect of Leptin on Blood Lipids: A Mendelian Randomization Study

Circulation ◽

10.1161/circ.137.suppl_1.p199 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Luqi Shen ◽

Jose Cordero ◽

Jia-Sheng Wang ◽

Ye Shen ◽

Changwei Li

Keyword(s):

Physical Activity ◽

Alcohol Consumption ◽

Alcohol Drinking ◽

Mendelian Randomization ◽

Density Lipoprotein ◽

Sensitivity Analyses ◽

Lipid Lowering ◽

Glucose Lowering ◽

Adjusted Model ◽

Age And Sex

Objective: The current study aimed to evaluate the relation between leptin and serum lipids, and to explore whether alcohol consumption modifies the effect of leptin on lipids. Method: We conducted a Mendelian randomization analysis to the baseline data for 3,780 participants of the Framingham Heart Study Generation III cohort. A genetic risk score (GRS) for leptin was generated by summing leptin increasing alleles of 3 single-nucleotide polymorphisms, weighted by their corresponding effect sizes on leptin reported by Kilpelainen et al. For those taking lipid lowering medications, total cholesterol (TC) was adjusted as TC/0.8, and low density lipoprotein (LDL) was imputed by replacing the adjusted TC into the Friedewald equation. Leptin and triglycerides (TG) were log transformed. Associations between the GRS and leptin, leptin and imputed lipids, and GRS and imputed lipids were assessed, respectively, by multivariate linear regression models, controlling for age and sex in basic model and additionally controlling for education, smoking, drinking, and physical activity in the fully adjusted model. Interactions between the GRS and alcohol drinking was evaluated by adding an interaction term, GRS*drinking, in the fully adjusted model. Sensitivity analyses were performed among those not taking lipid or glucose lowering medications. Result: In univariate analyses, the GRS was significantly associated with leptin (Beta=1.44, P =4.55E-4), but not with age ( P =0.33), sex ( P =0.62), education ( P =0.37), smoking ( P =0.59), drinking ( P =0.42), or physical activity ( P =0.80). Leptin was significantly associated with age and sex adjusted LDL (Beta=7.29, P =5.95E-38), high density lipoprotein (HDL) (Beta=-4.30, P =4.35E-62), TG (Beta=0.22, P =1.05E-119), and TC (Beta=8.06, P =1.72E-36). The GRS for leptin was associated with HDL (Beta=-16.72, P =0.01), but not LDL (Beta=2.64, P =0.85), TG (Beta=-0.35, P =0.16), or TC (Beta=-23.34, P =0.15), in partially adjusted model. In the fully adjusted model, association between the GRS and HDL was still significant (Beta=-16.70, P =0.01). When stratified by drinking status, the GRS for leptin was significantly associated with reduced LDL (Beta=-99.26, P =0.02), TG (Beta=-2.4, P =0.002), and TC (Beta=-156.10, P =0.001) among non-current drinkers, and reduced HDL (Beta=-19.98, P =0.005) among current drinkers, adjusting for age and sex. After further adjustment, these associations were still significant. In the fully adjusted model, significant interactions between the GRS and alcohol drinking were identified for LDL ( P =0.02), TG ( P =0.005), and TC ( P =0.008). Sensitivity analyses among those not taking lipid or glucose lowering medications revealed similar associations. Conclusion: Out study provided evidence for a causal relationship between leptin and lipids, and an interaction effect of alcohol drinking on leptin and lipids associations.

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Association of physical activity and sedentary behavior with type 2 diabetes and glycemic traits: a two-sample Mendelian randomization study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001896 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001896

Author(s):

Christa Meisinger ◽

Jakob Linseisen ◽

Michael Leitzmann ◽

Hansjoerg Baurecht ◽

Sebastian Edgar Baumeister

Keyword(s):

Physical Activity ◽

Type 2 Diabetes ◽

Sedentary Behavior ◽

Mendelian Randomization ◽

Fasting Glucose ◽

Vigorous Physical Activity ◽

Model Assessment ◽

Homeostasis Model Assessment ◽

A Genome

IntroductionObservational studies suggest that physical activity lowers and sedentary behavior increases the risk of type 2 diabetes. Despite of some supportive trial data for physical activity, it is largely unresolved whether these relations are causal or due to bias.ObjectiveWe investigated the associations between accelerometer-based physical activity and sedentary behavior with type 2 diabetes and several glycemic traits using two-sample Mendelian randomization analysis.Research design and methodsSingle nucleotide polymorphisms (SNPs) associated at p<5×10−8 with accelerometer-based physical activity average accelerations, vigorous physical activity (fraction of accelerations >425 milligravities), and sedentary behavior (metabolic equivalent task ≤1.5) in a genome-wide analysis of the UK Biobank served as instrumental variables.OutcomesType 2 diabetes, hemoglobin A1c (HbA1c), fasting glucose, homeostasis model assessment of beta-cell function (HOMA-B), and homeostasis model assessment of insulin resistance (HOMA-IR).ResultsPhysical activity and sedentary behavior were unrelated to type 2 diabetes, HbA1c, fasting glucose, HOMA-B, and HOMA-IR. The inverse variance weighted ORs per SD increment for the association between average accelerations and vigorous physical activity with type 2 diabetes were 1.00 (95% CI 0.94 to 1.07, p=0.948) and 0.83 (95% CI 0.56 to 1.23, p=0.357), respectively. These results were confirmed by sensitivity analyses using alternative MR-methods to test the robustness of our findings.ConclusionsBased on these results, genetically predicted objectively measured average or vigorous physical activity and sedentary behavior is not associated with type 2 diabetes risk or with glycemic traits in the general population. Further research is required to deepen the understanding of the biological pathways of physical activity.

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