Univariable and Multivariable Two-Sample Mendelian Randomization Investigating the Effects of Leisure Sedentary Behaviors on the Risk of Lung Cancer

Background:Leisure sedentary behaviors (LSB) are widespread, and observational studies have provided emerging evidence that LSB play a role in the development of lung cancer (LC). However, the causal inference between LSB and LC remains unknown.Methods: We utilized univariable (UVMR) and multivariable two-sample Mendelian randomization (MVMR) analysis to disentangle the effects of LSB on the risk of LC. MR analysis was conducted with genetic variants from genome-wide association studies of LSB (408,815 persons from UK Biobank), containing 152 single-nucleotide polymorphisms (SNPs) for television (TV) watching, 37 SNPs for computer use, and four SNPs for driving, and LC from the International Lung Cancer Consortium (11,348 cases and 15,861 controls). Multiple sensitivity analyses were further performed to verify the causality.Results: UVMR demonstrated that genetically predisposed 1.5-h increase in LSB spent on watching TV increased the odds of LC by 90% [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.44–2.50; p < 0.001]. Similar trends were observed for squamous cell lung cancer (OR, 1.97; 95%CI, 1.31–2.94; p = 0.0010) and lung adenocarcinoma (OR, 1.64; 95%CI 1.12–2.39; p = 0.0110). The causal effects remained significant after adjusting for education (OR, 1.97; 95%CI, 1.44–2.68; p < 0.001) and body mass index (OR, 1.86; 95%CI, 1.36–2.54; p < 0.001) through MVMR approach. No association was found between prolonged LSB spent on computer use and driving and LC risk. Genetically predisposed prolonged LSB was additionally correlated with smoking (OR, 1.557; 95%CI, 1.287–1.884; p < 0.001) and alcohol consumption (OR, 1.010; 95%CI, 1.004–1.016; p = 0.0016). Consistency of results across complementary sensitivity MR methods further strengthened the causality.Conclusion: Robust evidence was demonstrated for an independent, causal effect of LSB spent on watching TV in increasing the risk of LC. Further work is necessary to investigate the potential mechanisms.

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Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

International Journal of Epidemiology ◽

10.1093/ije/dyaa266 ◽

2021 ◽

Author(s):

Fernando Pires Hartwig ◽

Kate Tilling ◽

George Davey Smith ◽

Deborah A Lawlor ◽

Maria Carolina Borges

Keyword(s):

Waist Circumference ◽

Genetic Variants ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Real Data ◽

Sensitivity Analyses ◽

Effect Estimate ◽

Genome Wide Association Studies ◽

Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

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Mendelian randomisation study of smoking exposure in relation to breast cancer risk

British Journal of Cancer ◽

10.1038/s41416-021-01432-8 ◽

2021 ◽

Author(s):

Hanla A. Park ◽

Sonja Neumeyer ◽

Kyriaki Michailidou ◽

Manjeet K. Bolla ◽

Qin Wang ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Smoking Exposure

Abstract Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

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Depression and Osteoporosis: A Mendelian Randomization Study

Calcified Tissue International ◽

10.1007/s00223-021-00886-5 ◽

2021 ◽

Author(s):

Bin He ◽

Qiong Lyu ◽

Lifeng Yin ◽

Muzi Zhang ◽

Zhengxue Quan ◽

...

Keyword(s):

Observational Studies ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Meta Analysis ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Reverse Causality ◽

Mineral Density

AbstractObservational studies suggest a link between depression and osteoporosis, but these may be subject to confounding and reverse causality. In this two-sample Mendelian randomization analysis, we included the large meta-analysis of genome-wide association studies for depression among 807,553 individuals (246,363 cases and 561,190 controls) of European descent, the large meta-analysis to identify genetic variants associated with femoral neck bone mineral density (FN-BMD), forearm BMD (FA-BMD) and lumbar spine BMD (LS-BMD) among 53,236 individuals of European ancestry, and the GWAS summary data of heel BMD (HE-BMD) and fracture among 426,824 individuals of European ancestry. The results revealed that genetic predisposition towards depression showed no causal effect on FA-BMD (beta-estimate: 0.091, 95% confidence interval [CI] − 0.088 to 0.269, SE:0.091, P value = 0.320), FN-BMD (beta-estimate: 0.066, 95% CI − 0.016 to 0.148, SE:0.042, P value = 0.113), LS-BMD (beta-estimate: 0.074, 95% CI − 0.029 to 0.177, SE:0.052, P value = 0.159), HE-BMD (beta-estimate: 0.009, 95% CI − 0.043 to 0.061, SE:0.027, P value = 0.727), or fracture (beta-estimate: 0.008, 95% CI − 0.071 to 0.087, SE:0.041, P value = 0.844). These results were also confirmed by multiple sensitivity analyses. Contrary to the findings of observational studies, our results do not reveal a causal role of depression in osteoporosis or fracture.

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Type 2 Diabetes and Glycemic Traits Are Not Causal Factors of Osteoarthritis: A Two-Sample Mendelian Randomization Analysis

Frontiers in Genetics ◽

10.3389/fgene.2020.597876 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhiyong Cui ◽

Hui Feng ◽

Baichuan He ◽

Yong Xing ◽

Zhaorui Liu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Association Studies ◽

Causal Effects ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Knee Oa ◽

Increased Risk

BackgroundIt remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA).MethodsHere, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identified single-nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG), and 2-h postprandial glucose (2hGlu) from genome-wide association studies (GWAS). We used the MR inverse variance weighted (IVW), the MR–Egger method, the weighted median (WM), and the Robust Adjusted Profile Score (MR.RAPS) to reveal the associations of T2D, FG, and 2hGlu with hip and knee OA risks. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.ResultsWe did not find statistically significant causal effects of genetically increased T2D risk, FG, and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR–Egger OR = 1.1708, 95% CI 0.9469–1.4476, p = 0.1547). It was confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR–Egger, intercept = −0.0105, p = 0.1367). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR–Egger Q = 30.1362, I2 < 0.0001, p = 0.6104).ConclusionOur MR study did not support causal effects of a genetically increased T2D risk, FG, and 2hGlu on hip and knee OA risk.

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Type 2 diabetes and glycemic traits are not causal factors of osteoarthritis: A two-sample Mendelian randomization analysis

10.21203/rs.3.rs-37242/v1 ◽

2020 ◽

Author(s):

Zhiyong Cui ◽

Hui Feng ◽

Baichuan He ◽

Yong Xing ◽

Zhaorui Liu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Association Studies ◽

Causal Effects ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Knee Oa ◽

Increased Risk

Abstract Background: It remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA). Methods: Here, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identified single nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG) and 2-hour postprandial glucose (2hGlu) from genome-wide association studies (GWAS) . We used MR inverse variance weighted (IVW), the MR-Egger method, the weighted median (WM) and Robust Adjusted Profile Score (MR.RAPS) to reveal the associations of T2D, FG and 2hGlu with hip and knee OA risk. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.Results: We did not find statistically significant causal effects of genetically increased T2D risk, FG and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR-Egger OR=0.9536, 95% CI 0.5585 to 1.6283, p=0.8629). It was confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR-Egger, intercept=-0.0032, p=0.8518). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR-Egger Q=40.5481, I2=0.1368, p=0.2389). Conclusions: Our MR study did not support causal effects of a genetically increased T2D risk, FG and 2hGlu on hip and knee OA risk.

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Impact of Liability to Periodontitis on Glycemic Control and Type II Diabetes Risk: A Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.767577 ◽

2021 ◽

Vol 12 ◽

Author(s):

Parth D. Shah ◽

C. M. Schooling ◽

Luisa N. Borrell

Keyword(s):

Type Ii Diabetes ◽

Mendelian Randomization ◽

Fasting Glucose ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Type Ii ◽

Nucleotide Polymorphisms ◽

Causal Association ◽

East Asians

While the association of periodontitis with Type II diabetes (T2DM) is well-established, the causal relationship remains uncertain. We examined the causal association of periodontitis with glycemic traits (HbA1c, fasting glucose, and fasting insulin) and T2DM using Mendelian randomization (MR) taking advantage of large genome-wide association studies of European and East Asian adults, i.e., the UK Biobank (n ≈ 350,000) (HbA1c), trans-ancestral MAGIC (HbA1c, fasting glucose, and insulin), and DIAMANTE (74,124 cases/824,006 controls), and AGEN for T2DM in Europeans and East Asians, respectively. Periodontitis was instrumented using single-nucleotide polymorphisms (SNPs), strongly and independently predicting liability to periodontitis in each ancestry group. SNP-specific Wald estimates were combined using inverse variance weighting. Sensitivity analyses were performed using the weighted median and MR-Egger with meta-analysis of MR estimates for Europeans and East Asians. Genetically instrumented liability to periodontitis was not associated with glycemic traits or T2DM in either ancestry or when ancestry specific estimates were meta-analyzed. Our findings do not support a causal association of liability to periodontitis with glycemic traits or T2DM. However, further research is required confirming these findings among other racial/ethnic groups, especially groups who carry a heavy burden of both periodontitis and T2DM.

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Gluten-free Diet Reduces the Risk of Irritable Bowel Syndrome: A Mendelian Randomization Analysis

Frontiers in Genetics ◽

10.3389/fgene.2021.684535 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuhao Sun ◽

Xuejie Chen ◽

Shuyang Wang ◽

Minzi Deng ◽

Ying Xie ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Protective Factor ◽

Mendelian Randomization ◽

Association Studies ◽

Gluten Free Diet ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Gluten Free ◽

Nucleotide Polymorphisms ◽

Irritable Bowel

Background: Whether a gluten-free diet (GFD) is a cause of irritable bowel syndrome (IBS) remains controversial. We aim at exploring the causal relationship between gluten intake and IBS within Mendelian randomization (MR) design.Methods: We conducted a two-sample MR and selected single-nucleotide polymorphisms (SNPs) associated with GFD as instrumental variables (IVs). SNPs and genetic associations with GFD and IBS were obtained from the latest genome-wide association studies (GWAS) in Europeans (GFD: cases: 1,376; controls: 63,573; IBS: cases:1,121; controls: 360,073). We performed inverse variance weighting (IVW) as the primary method with several sensitivity analyses like MR-Egger and MR-PRESSO for quality control. The above analyses were re-run using another large dataset of IBS, as well as changing the p-value threshold when screening IVs, to verify the stability of the results.Results: The final estimate indicated significant causal association [per one copy of effect allele predicted log odds ratio (OR) change in GFD intake: OR = 0.97, 95% confidence interval (CI) 0.96 to 0.99, p < 0.01] without heterogeneity statistically (Q = 2.48, p = 0.78) nor horizontal pleiotropy biasing the causality (p = 0.92). Consistent results were found in validation analyses. Results of MR Steiger directionality test indicated the accuracy of our estimate of the causal direction (Steiger p < 0.001).Conclusion: GFD might be a protective factor of IBS. Therefore, we suggest taking a diet of lower gluten intake into account in IBS prevention and clinical practice.

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Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study

International Journal of Epidemiology ◽

10.1093/ije/dyy284 ◽

2018 ◽

Vol 48 (5) ◽

pp. 1416-1424 ◽

Cited By ~ 16

Author(s):

Xia Jiang ◽

Niki L Dimou ◽

Kawthar Al-Dabhani ◽

Sarah J Lewis ◽

Richard M Martin ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Vitamin D ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Common Genetic Variants ◽

Breast And Prostate Cancer

Abstract Background Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power. Methods We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods. Results We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97–1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94–1.07), P = 0.99] or ER− [1.02 (0.90–1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93–1.07), P = 0.99] or the advanced subtype [1.02 (0.90–1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy. Conclusions Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.

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The causal effect of interleukin-17 on the risk of psoriatic arthritis: a Mendelian randomization study

Rheumatology ◽

10.1093/rheumatology/keaa629 ◽

2020 ◽

Author(s):

Dongze Wu ◽

Priscilla Wong ◽

Steven H M Lam ◽

Edmund K Li ◽

Ling Qin ◽

...

Keyword(s):

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Preliminary Evidence ◽

Interleukin 17 ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Tnf Α ◽

Weighted Median

Abstract Objective To determine causal associations between genetically predicted TNF-α, IL-12p70 and IL-17 levels and risk of PsA. Methods The publicly available summary-level findings from genome-wide association studies (GWAS) was used to identify loci influencing normal physiological concentrations of TNF-α, IL-12p70 and IL-17 (n = 8293) among healthy individuals as exposure and a GWAS for PsA from the UK Biobank (PsA = 900, control = 462 033) as the outcome. A two-sample Mendelian randomization (MR) analysis was performed using the inverse-variance weighted (IVW), weighted median and MR–Egger regression methods. Sensitivity analysis and MR–Egger regression analysis were performed to evaluate the heterogeneity and pleiotropic effects of each variant. Results Single-nucleotide polymorphisms (SNPs) at genome-wide significance from GWASs on TNF-α, IL-12p70 and IL-17 were identified as the instrumental variables. The IVW method indicated a causal association between increased IL-17 level and risk of PsA (β = −0.00186 per allele, s.e. = 0.00043, P = 0.002). Results were consistent in the weighted median method (β = −0.00145 per allele, s.e. = 0.00059, P = 0.014) although the MR–Egger method suggested a non-significant association (β = −0.00133 per allele, s.e. = 0.00087; P = 0.087). Single SNP MR results revealed that the C allele of rs117556572 was robustly associated with risk of PsA (β = 0.00210, s.e. = 0.00069, P = 0.002). However, no evidence for a causal effect was observed between TNF-α, IL-12p70, decreased IL-17 levels and risk of PsA. Conclusion Our findings provide preliminary evidence that genetic variants predisposing to higher physiological IL-17 level are associated with decreased risk of PsA.

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Examining the Causal Inference of Leptin and Soluble Plasma Leptin Receptor Levels on Schizophrenia: A Mendelian Randomization Study

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.753224 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guoqing Chen ◽

Qiuling Wang ◽

Ranran Xue ◽

Xia Liu ◽

Hao Yu

Keyword(s):

Large Scale ◽

Leptin Receptor ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Unit Increase ◽

Plasma Leptin

Background: Observational studies that have supported the role of the leptin level in schizophrenia (SCZ) risk are conflicting. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether the circulating leptin and soluble plasma leptin receptor (sOB-R) levels play a causal role in SCZ risk.Methods: We first selected five independent single-nucleotide polymorphisms (SNPs) associated with the circulating leptin level and three independent SNPs associated with the sOB-R level from two genome-wide association studies (GWASs) of European individuals. Then, we extracted their associations with SCZ using a large-scale GWAS that consisted of 40,675 patients with SCZ and 64,643 controls of European ancestry. We performed an MR analysis using the inverse variance-weighted (IVW) method to examine the causal effect of leptin on SCZ risk. Moreover, we performed sensitivity analyses to verify our MR results using the weighted median and MR-Egger methods.Results: According to the IVW method, genetically predicted circulating leptin levels were not associated with SCZ risk (OR = 1.98, for per 1-SD unit increase in leptin level; 95% CI, 0.87–4.53; p = 0.10). In addition, the sOB-R level showed no causal effect on the SCZ risk using IVW (OR = 0.98 for per 1-SD unit increase in sOB-R level; 95% CI, 0.97–1.00; p = 0.06). Our sensitivity analysis results confirmed our MR findings.Conclusions: By estimating the causal effect of leptin on SCZ risk using the MR methods, we identified no effect of genetically predicted circulating leptin or the sOB-R level on SCZ. As such, our study suggests that leptin might not be a risk factor for SCZ.

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