scholarly journals Physical activity and risk of lung cancer: a two-sample Mendelian randomization study

2019 ◽  
Author(s):  
Sebastian E Baumeister ◽  
Michael F Leitzmann ◽  
Martin Bahls ◽  
Christa Meisinger ◽  
Christopher I Amos ◽  
...  
Keyword(s):  
Physical Activity ◽  
Lung Cancer ◽  
Mendelian Randomization ◽  
Vigorous Physical Activity ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Q Value ◽  
Genome Wide ◽  
Never Smokers ◽  
Genetic Instruments

AbstractObservational studies have suggested that physical activity might lower the risk of lung cancer in former and current smokers but not in never smokers. Using genetic instruments for self-reported and accelerometer-measured physical activity traits implemented through two-sample Mendelian randomization (MR), we sought to strengthen the evidence for causality. We used 18 genome-wide significant (P < 5×10−8) single nucleotide polymorphisms (SNPs) for self-reported moderate-to-vigorous physical activity and seven SNPs for accelerometer-measured (‘average acceleration’) physical activity from up to 377,234 UK Biobank participants and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR analysis suggested no effect of self-reported physical activity (odds ratio (OR) [95% confidence interval (CI)] = 0.67 [0.42-1.05], P-value = 0.081, Q-value = 0.243) and accelerometer-measured activity (OR [95% CI] = 0.98 [0.93-1.03], P-value = 0.372,Q-value = 0.562) on lung cancer. There was no evidence for associations of physical activity with histologic types and lung cancer in ever and never smokers. Replication analysis using genetic instruments from a different genome-wide study and sensitivity analysis to address potential pleiotropic effects led to no substantive change in estimates. These findings do not support a protective relationship between physical activity and the risk of lung cancer.SignificanceThe present study provides little evidence that recommending physical activity would help to prevent lung cancer.

scholarly journals Genetically Determined Physical Activity and Its Association with Circulating Blood Cells

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 908 ◽  
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.

scholarly journals Physical activity and risk of Alzheimer disease

Neurology ◽  
2020 ◽  
Vol 95 (13) ◽  
pp. e1897-e1905
Author(s):  
Sebastian E. Baumeister ◽  
André Karch ◽  
Martin Bahls ◽  
Alexander Teumer ◽  
Michael F. Leitzmann ◽  
...  
Keyword(s):  
Physical Activity ◽  
Alzheimer Disease ◽  
Association Studies ◽  
Vigorous Physical Activity ◽  
Primary Study ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Inverse Variance ◽  
Study Population

ObjectiveEvidence from observational studies for the effect of physical activity on the risk of Alzheimer disease (AD) is inconclusive. We performed a 2-sample mendelian randomization analysis to examine whether physical activity is protective for AD.MethodsSummary data of genome-wide association studies on physical activity and AD were used. The primary study population included 21,982 patients with AD and 41,944 cognitively normal controls. Eight single nucleotide polymorphisms (SNPs) known at p < 5 × 10−8 to be associated with average accelerations and 8 SNPs associated at p < 5 × 10−7 with vigorous physical activity (fraction of accelerations >425 milligravities) served as instrumental variables.ResultsThere was no association between genetically predicted average accelerations with the risk of AD (inverse variance weighted odds ratio [OR] per SD increment: 1.03, 95% confidence interval 0.97–1.10, p = 0.332). Genetic liability for fraction of accelerations >425 milligravities was unrelated to AD risk.ConclusionThe present study does not support a causal association between physical activity and risk of AD.

Powerful three-sample genome-wide design and robust statistical inference in summary-data Mendelian randomization

2019 ◽  
Vol 48 (5) ◽  
pp. 1478-1492 ◽  
Author(s):  
Qingyuan Zhao ◽  
Yang Chen ◽  
Jingshu Wang ◽  
Dylan S Small
Keyword(s):  
Odds Ratio ◽  
Statistical Power ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Density Lipoprotein ◽  
P Value ◽  
Genome Wide ◽  
A Genome ◽  
Summary Data ◽  
Genetic Instruments

Abstract Background Summary-data Mendelian randomization (MR) has become a popular research design to estimate the causal effect of risk exposures. With the sample size of GWAS continuing to increase, it is now possible to use genetic instruments that are only weakly associated with the exposure. Development We propose a three-sample genome-wide design where typically 1000 independent genetic instruments across the whole genome are used. We develop an empirical partially Bayes statistical analysis approach where instruments are weighted according to their strength; thus weak instruments bring less variation to the estimator. The estimator is highly efficient with many weak genetic instruments and is robust to balanced and/or sparse pleiotropy. Application We apply our method to estimate the causal effect of body mass index (BMI) and major blood lipids on cardiovascular disease outcomes, and obtain substantially shorter confidence intervals (CIs). In particular, the estimated causal odds ratio of BMI on ischaemic stroke is 1.19 (95% CI: 1.07–1.32, P-value <0.001); the estimated causal odds ratio of high-density lipoprotein cholesterol (HDL-C) on coronary artery disease (CAD) is 0.78 (95% CI: 0.73–0.84, P-value <0.001). However, the estimated effect of HDL-C attenuates and become statistically non-significant when we only use strong instruments. Conclusions A genome-wide design can greatly improve the statistical power of MR studies. Robust statistical methods may alleviate but not solve the problem of horizontal pleiotropy. Our empirical results suggest that the relationship between HDL-C and CAD is heterogeneous, and it may be too soon to completely dismiss the HDL hypothesis.

scholarly journals Investigating the causal relationship between physical activity and chronic back pain: a bidirectional two-sample Mendelian randomization study

2021 ◽  
Author(s):  
Shaowei Gao ◽  
Huaqiang Zhou ◽  
Siyu Luo ◽  
Xiaoying Cai ◽  
Fang Ye ◽  
...  
Keyword(s):  
Physical Activity ◽  
Back Pain ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Chronic Back Pain ◽  
Vigorous Physical Activity ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Instruments

Background Recent observational studies have reported a negative association between physical activity and chronic back pain (CBP), but the causality of the association remains unknown. We introduce bidirectional Mendelian randomization (MR) to assess potential causal inference between physical activity and CBP. Methods The two-sample MR was used with independent genetic variants associated with physical activity phenotypes and CBP as genetic instruments from large genome-wide association studies (GWASs) on individuals of European ancestry. The effects of both directions (physical activity to CBP and CBP to physical activity) were examined. Inverse variance-weighted meta-analysis and alternate methods (weighted median and MR-Egger) were used to combine the MR estimates of the genetic instruments. Multiple sensitivity analyses were conducted to examine the robustness of the results. Results For primary analysis, instrumental variables were extracted from 337,234 participants for physical activity (the same as the outcome cohort) and 158,025 participants (29,531 cases) for CBP, while the outcome cohort for CBP included 117,404 participants (80,588 cases). No evidence of a causal relationship was found in the direction of physical activity to CBP (odds ratio [OR], 0.98; 95% CI, 0.85-1.13; P = 0.81). In contrast, a negative causal relationship in the direction of CBP to physical activity was detected (β = -0.07; 95% CI, -0.12 to -0.01; P = 0.02), implying a reduction in moderate-vigorous physical activity (approximately 146 MET-minutes/week) for participants with CBP relative to controls. Conclusions The negative relationship between physical activity and CBP is probably derived from the reduced physical activity of patients experiencing CBP rather than the protective effect of physical activity on CBP.

scholarly journals Testing Causal Bidirectional Influences between Physical Activity and Depression using Mendelian Randomization

2018 ◽  
Author(s):  
Karmel W. Choi ◽  
Chia-Yen Chen ◽  
Murray B. Stein ◽  
Yann C. Klimentidis ◽  
Min-Jung Wang ◽  
...  
Keyword(s):  
Physical Activity ◽  
Protective Factor ◽  
Mendelian Randomization ◽  
Significant Snps ◽  
Sensitivity Analyses ◽  
Inverse Association ◽  
Effective Prevention ◽  
Genome Wide ◽  
Average Acceleration ◽  
Genetic Instruments

AbstractBackground:Burgeoning evidence from randomized controlled trials and prospective cohort studies suggests that physical activity protects against depression, pointing to a potential modifiable target for prevention. However, the direction of this inverse association is not clear: physical activity may reduce risk for depression, and/or depression may result in decreased physical activity. Here, we used bidirectional two-sample Mendelian randomization (MR) to test causal influences between physical activity and depression.Methods:For genetic instruments, we selected independent top SNPs associated with major depressive disorder (MDD, N = 143,265) and two physical activity phenotypes—self-reported (N = 377,234) and objective accelerometer-based (N = 91,084)—from the largest available, non-overlapping genome-wide association results. We used two sets of genetic instruments: (1) only SNPs previously reported as genome-wide significant, and (2) top SNPs meeting a more relaxed threshold (p < 1×10-7). For each direction of influence, we combined the MR effect estimates from each instrument SNP using inverse variance weighted (IVW) meta-analysis, along with other standard MR methods such as weighted median, MR-Egger, and MR-PRESSO.Results:We found evidence for protective influences of accelerometer-based activity on MDD (IVW odds ratio (OR) = 0.74 for MDD per 1 SD unit increase in average acceleration, 95% confidence interval (CI) = 0.59-0.92, p =.006) when using SNPs meeting the relaxed threshold (i.e., 10 versus only 2 genome-wide significant SNPs, which provided insufficient data for sensitivity analyses). In contrast, we found no evidence for negative influences of MDD on accelerometer-based activity (IVW b = 0.04 change in average acceleration for MDD versus control status, 95% CI = −0.43-0.51, p =.87). Furthermore, we did not see evidence for causal influences between self-reported activity and MDD, in either direction and regardless of instrument SNP criteria.Discussion:We apply MR for the first time to examine causal influences between physical activity and MDD. We discover that objectively measured—but not self-reported—physical activity is inversely associated with MDD. Of note, prior work has shown that accelerometer-based physical activity is more heritable than self-reported activity, in addition to being more representative of actual movement. Our findings validate physical activity as a protective factor for MDD and point to the importance of objective measurement of physical activity in epidemiological studies in relation to mental health. Overall, this study supports the hypothesis that enhancing physical activity is an effective prevention strategy for depression.

scholarly journals Investigating the Causal Relationship Between Physical Activity and Chronic Back Pain: A Bidirectional Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Shaowei Gao ◽  
Huaqiang Zhou ◽  
Siyu Luo ◽  
Xiaoying Cai ◽  
Fang Ye ◽  
...  
Keyword(s):  
Physical Activity ◽  
Back Pain ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Chronic Back Pain ◽  
Association Studies ◽  
Vigorous Physical Activity ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Genetic Instruments

Background: Recent observational studies have reported a negative association between physical activity and chronic back pain (CBP), but the causality of the association remains unknown. We introduce bidirectional Mendelian randomization (MR) to assess potential causal inference between physical activity and CBP.Materials and Methods: This two-sample MR used independent genetic variants associated with physical activity and CBP as genetic instruments from large genome-wide association studies (GWASs). The effects of both directions (physical activity to CBP and CBP to physical activity) were examined. Inverse variance-weighted meta-analysis and alternate methods (weighted median and MR-Egger) were used to combine the MR estimates of the genetic instruments. Multiple sensitivity analyses were conducted to examine the robustness of the results.Results: The MR set parallel GWAS cohorts, among which, those involved in the primary analysis were comprised of 337,234 participants for physical activity and 158,025 participants (29,531 cases) for CBP. No evidence of a causal relationship was found in the direction of physical activity to CBP [odds ratio (OR), 0.98; 95% CI, 0.85–1.13; p = 0.81]. In contrast, a negative causal relationship in the direction of CBP to physical activity was detected (β = −0.07; 95% CI, −0.12 to −0.01; p = 0.02), implying a reduction in moderate-vigorous physical activity (approximately 146 MET-minutes/week) for participants with CBP relative to controls.Conclusion: The negative relationship between physical activity and CBP is probably derived from the reduced physical activity of patients experiencing CBP rather than the protective effect of physical activity on CBP.

No causal effects of plasma homocysteine levels on the risk of coronary heart disease or acute myocardial infarction: A Mendelian randomization study

2019 ◽  
pp. 204748731989467 ◽  
Author(s):  
Liu Miao ◽  
Guo-Xiong Deng ◽  
Rui-Xing Yin ◽  
Rong-Jun Nie ◽  
Shuo Yang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Mendelian Randomization ◽  
Plasma Homocysteine ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Artery Disease

Background Although many observational studies have shown an association between plasma homocysteine levels and cardiovascular diseases, controversy remains. In this study, we estimated the role of increased plasma homocysteine levels on the etiology of coronary heart disease and acute myocardial infarction. Methods A two-sample Mendelian randomization study on disease was conducted, i.e. “coronary heart disease” ( n = 184,305) and “acute myocardial infarction” ( n = 181,875). Nine single nucleotide polymorphisms, which were genome-wide significantly associated with plasma homocysteine levels in 57,644 subjects from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium genome-wide association study and were known to be associated at p < 5×10–8, were used as an instrumental variable. Results None of the nine single nucleotide polymorphisms were associated with coronary heart disease or acute myocardial infarction ( p > 0.05 for all). Mendelian randomization analysis revealed no causal effects of plasma homocysteine levels, either on coronary heart disease (inverse variance weighted; odds ratio = 1.015, 95% confidence interval = 0.923–1.106, p = 0.752) or on acute myocardial infarction (inverse variance weighted; odds ratio = 1.037, 95% confidence interval = 0.932–1.142, p = 0.499). The results were consistent in sensitivity analyses using the weighted median and Mendelian randomization-Egger methods, and no directional pleiotropy ( p = 0.213 for coronary heart disease and p = 0.343 for acute myocardial infarction) was observed. Sensitivity analyses confirmed that plasma homocysteine levels were not significantly associated with coronary heart disease or acute myocardial infarction. Conclusions The findings from this Mendelian randomization study indicate no causal relationship between plasma homocysteine levels and coronary heart disease or acute myocardial infarction. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.

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

2016 ◽  
Vol 8 ◽  
pp. GEG.S38289 ◽  
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.

scholarly journals Programmed Death Ligand 2 Gene Polymorphisms Are Associated With Lung Adenocarcinoma Risk in Female Never-Smokers

2021 ◽  
Vol 11 ◽  
Author(s):  
Sheng-Kai Liang ◽  
Li-Hsin Chien ◽  
Gee-Chen Chang ◽  
Ying-Huang Tsai ◽  
Wu-Chou Su ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Pulmonary Tuberculosis ◽  
Lung Adenocarcinoma ◽  
Genome Wide Association Study ◽  
Lung Cancer Screening ◽  
Tuberculosis Infection ◽  
Eqtl Analysis ◽  
Nucleotide Polymorphisms ◽  
Programmed Death ◽  
Never Smokers

ObjectivesLung cancer in never-smokers is a distinct disease associated with a different genomic landscape, pathogenesis, risk factors, and immune checkpoint inhibitor responses compared to those observed in smokers. This study aimed to identify novel single nucleotide polymorphisms (SNPs) of programmed death-1 (encoded by PDCD1) and its ligands, programmed death ligand 1 (CD274) and 2 (PDCD1LG2), associated with lung cancer risk in never-smoking women.Materials and MethodsDuring September 2002 and July 2012, we enrolled never-smoking female patients with lung adenocarcinoma (LUAD) (n=1153) and healthy women (n=1022) from six tertiary hospitals in Taiwan. SNP data were obtained and analyzed from the genome-wide association study dataset and through an imputation method. The expression quantitative trait loci (eQTL) analysis was performed in both tumor and non-tumor tissues for the correlation between genetic expression and identified SNPs.ResultsA total of 12 PDCD1LG2 SNPs related to LUAD risk were identified in never-smoking women, including rs2381282, rs4742103, rs4237162, rs4742104, rs12237624, rs78096119, rs6476988, rs7857315, rs10975178, rs7854413, rs56001683, and rs7858319. Among them, six tagged PDCD1LG2 SNPs rs2381282, rs4742103, rs4237162, rs4742104, rs78096119, and rs56001683 were significantly associated with LUAD risk. Specifically, two PDCD1LG2 SNPs, rs12237624 and rs78096119, were associated with previous pulmonary tuberculosis infection in relation to LUAD susceptibility. Through an eQTL assay, we found that rs2381282 (p &lt; 0.001), rs12237624 (p = 0.019), and rs78096119 (p = 0.019) were associated with the expression levels of programed death ligand 2.ConclusionsNovel SNPs of programed death ligand 2 associated with lung adenocarcinoma risk were identified. Among them, two SNPs were associated with pulmonary tuberculosis infection in relation to lung adenocarcinoma susceptibility. These SNPs may help to stratify high-risk populations of never-smokers during lung cancer screening.

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