scholarly journals Causal Association of Coffee Consumption and Total, Knee, Hip and Self-Reported Osteoarthritis: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Yangchang Zhang ◽  
Jun Fan ◽  
Li Chen ◽  
Yang Xiong ◽  
Tingting Wu ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Coffee Consumption ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Knee Oa ◽  
Total Knee ◽  
Genetic Instruments

BackgroundThe causal association between coffee consumption and the risk of OA is limited. This study was conducted to identify the potential causal effects of coffee consumption on total, knee, hip, and self-reported OA.MethodsGenome-wide association studies (GWAS) of OA were derived from the UK Biobank, comprising 50,508 participants of European ancestry (10,083 with cases and 40,425 controls), and genetic data for specific diagnosed knee OA (4462 cases and 17,885 controls), hip OA (12,625 cases and 50,898 controls), and self-reported OA (12,658 cases and 50,898 controls). Primary and secondary genetic instruments (11 SNPs and 8 SNPs) were selected as instrumental variants from GWAS among 375,833 and 91,462 participants. Two-sample Mendelian randomization (MR) analyses were performed to test the effects of the selected single nucleotide polymorphisms (SNPs) and the OA risk. The causal effects were primarily estimated using weighted median and inverse-variance weighted method with several sensitivity analyses.ResultsThe MR analyses suggested that genetically predicted 1% increase of coffee consumption was associated with an increased risk of overall OA (OR:1.009, 95% CI:1.003-1.016), knee OA (OR:1.023, 95% CI:1.009-1.038), self-reported OA (OR:1.007, 95% CI:1.003-1.011), but not hip OA (OR: 1.012, 95%CI:0.999-1.024) using primary genetic instruments. Similar results were found when using secondary genetic instruments that genetically predicted coffee consumption (cups/day). Additionally, the sensitivity analyses for leave-one-out methods supported a robust association between exposure traits and OA.ConclusionOur findings indicate that genetically predicted coffee consumption exerts a causal effect on total, knee, and self-reported OA risk, but not at the hip. Further research is required to unravel the role of coffee consumption in OA prevention.

Causal association of adipokines with osteoarthritis: a Mendelian randomization study

Rheumatology ◽  
2020 ◽  
Author(s):  
Jiayao Fan ◽  
Jiahao Zhu ◽  
Lingling Sun ◽  
Yasong Li ◽  
Tianle Wang ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Knee Oa ◽  
Genome Wide ◽  
A Genome ◽  
Weighted Median

Abstract Objective This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. Methods Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. Results The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13–5.09] and weighted median (OR: 2.94, 95% CI: 1.23–6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01–1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18–10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03–1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. Conclusions An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

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

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.

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

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.

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis

2021 ◽  
pp. 135245852199307
Author(s):  
Adil Harroud ◽  
Ruth Ann Marrie ◽  
Kathryn C Fitzgerald ◽  
Amber Salter ◽  
Yi Lu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Causal Association ◽  
Major Depressive ◽  
Genetic Liability ◽  
Bidirectional Relationship ◽  
Genetic Instruments

Background: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. Objective: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). Methods: We selected genetic instruments associated with risk of MDD ( n = 660,937 cases; 1,453,489 controls) and MS ( n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. Results: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90–1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99–1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09–1.65) and MDD (OR = 1.08, 95% CI = 1.01–1.15). Conclusion: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

scholarly journals Plasma lipid levels and risk of primary open angle glaucoma: a genetic study using Mendelian randomization

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Mengqiao Xu ◽  
Shengguo Li ◽  
Jundong Zhu ◽  
Dawei Luo ◽  
Weitao Song ◽  
...  
Keyword(s):  
Primary Open Angle Glaucoma ◽  
Mendelian Randomization ◽  
Open Angle Glaucoma ◽  
Plasma Lipid ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Open Angle ◽  
Causal Association ◽  
Lipid Levels ◽  
A Genome

Abstract Background The causal effects of plasma lipid concentrations and the risk of primary open angle glaucoma (POAG) are still unclear. Thus, the purpose of this study was to identify, applying a two-sample Mendelian randomization (MR) analysis, whether plasma lipid concentrations are causally associated with the risk of POAG. Methods Two-sample MR analysis of data from a genome-wide association study (GWAS) was performed to investigate the causal role of plasma lipid levels and POAG. A total of 185 independent single-nucleotide polymorphisms (SNPs) associated with plasma lipid levels were selected as instrumental variables (IVs). The SNPs were obtained from a meta-analysis of GWAS based on 188,577 European-ancestry individuals for MR analyses. Association with POAG for the SNPs was obtained from a GWAS conducted among the United Kingdom (UK) Biobank study participants with a total of 463,010 European-ancestry individuals. Four MR methods (inverse variance weighted [IVW], weighted mode, weighted median, and MR-Egger regression) were applied to obtain the overall causal estimate for multiple, instrumental SNPs. Results Using the IVW analysis method, no evidence was found to support a causal association between plasma LDL-C level and POAG risk (β = − 0.00026; 95% CI = -0.00062, 0.00011; P = 0.165) with no significant heterogeneity among SNPs. The overall causal estimate between plasma LDL-C level and POAG was consistent using the other three MR methods. Using the four MR methods, no evidence of an association between plasma HDL-C (β = 0.00023; 95% CI = -0.00015, 0.00061; P = 0.238; IVW method) or TG levels (β = − 0.00028; 95% CI = -0.00071, 0.00015; P = 0.206; IVW method) and POAG risk was found. Sensitivity analyses did not reveal any sign of directional pleiotropy. Conclusions The present study did not find any evidence for a causal association between plasma lipid levels and POAG risk. Further research is needed to elucidate the potential biological mechanisms to provide a reasonable interpretation for these results.

scholarly journals Growth Differentiation Factor 15 Is Associated With Alzheimer’s Disease Risk

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng-Fei Wu ◽  
Xing-Hao Zhang ◽  
Ping Zhou ◽  
Rui Yin ◽  
Xiao-Ting Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Reverse Direction ◽  
Genome Wide Association Studies ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

scholarly journals Association of 25 hydroxyvitamin D concentration with risk of COVID-19: a Mendelian randomization study

2020 ◽  
Author(s):  
Di Liu ◽  
Qiuyue Tian ◽  
Jie Zhang ◽  
Haifeng Hou ◽  
Wei Wang ◽  
...  
Keyword(s):  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
25Ohd Concentration ◽  
25 Hydroxyvitamin D

Background In observational studies, 25 hydroxyvitamin D (25OHD) concentration has been associated with an increased risk of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether this association is causal. Methods We performed a two-sample Mendelian randomization (MR) to explore the causal relationship between 25OHD concentration and COVID-19, using summary data from the genome-wide association studies (GWASs) and using 25OHD concentration-related SNPs as instrumental variables (IVs). Results MR analysis did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity (odds ratio [OR]=1.136, 95% confidence interval [CI] 0.988-1.306, P=0.074; OR=0.889, 95% CI 0.549-1.439, P=0.632). Sensitivity analyses using different instruments and statistical models yielded similar findings, suggesting the robustness of the causal association. No obvious pleiotropy bias and heterogeneity were observed. Conclusion The MR analysis showed that there might be no linear causal relationship of 25OHD concentration with COVID-19 susceptibility and severity.

scholarly journals Coffee consumption and risk of breast cancer: a Mendelian Randomization study

2020 ◽  
Author(s):  
Merete Ellingjord-Dale ◽  
Nikos Papadimitriou ◽  
Michalis Katsoulis ◽  
Chew Yee ◽  
Niki Dimou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Random Effects ◽  
Mendelian Randomization ◽  
Coffee Consumption ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Inverse Association ◽  
Er Positive

AbstractBackgroundObservational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.MethodsWe conducted a two-sample Mendelian randomization randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations.ResultsOne cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR=0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07).ConclusionsThe results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak inverse association.

Maternal polycystic ovary syndrome and offspring birth weight: a Mendelian randomization study

2021 ◽  
Author(s):  
Yuexin Gan ◽  
Donghao Lu ◽  
Chonghuai Yan ◽  
Jun Zhang ◽  
Jian Zhao
Keyword(s):  
Birth Weight ◽  
Polycystic Ovary Syndrome ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Polycystic Ovary ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Ovary Syndrome ◽  
Genetic Instruments

Abstract Background Observational associations between maternal polycystic ovary syndrome (PCOS) and offspring birth weight (BW) have been inconsistent and the causal relationship is still uncertain. Objective We conducted a two-sample Mendelian randomization (MR) study to estimate the causal effect of maternal PCOS on offspring BW. Methods We constructed genetic instruments for PCOS with 14 single nucleotide polymorphisms (SNPs) which were identified in the genome-wide association study (GWAS) meta-analysis including 10,074 PCOS cases and 103,164 controls of European ancestry from seven cohorts. The genetic associations of these SNPs with the offspring BW were extracted from summary statistics estimated by the Early Growth Genetics (EGG) consortium (n = 406,063 European-ancestry individuals) using the weighted linear model (WLM), an approximation method of structural equation model (SEM), which separated maternal genetic effects from fetal genetic effects. We used a two-sample MR design to examine the causal relationship between maternal PCOS and offspring BW. Sensitivity analyses were conducted to assess the robustness of the MR results. Results We found little evidence for a causal effect of maternal PCOS on offspring BW (-6.1 g, 95% confidence interval [CI]: -16.8 g, 4.6 g). Broadly consistent results were found in the sensitivity analyses. Conclusion Despite the large scale of this study, our results suggested little causal effect of maternal PCOS on offspring BW. MR studies with a larger sample size of women with PCOS or more genetic instruments that would increase the variation of PCOS explained are needed in the future.

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