Rheumatoid arthritis decreases risk for Parkinson’s disease: a Mendelian randomization study

AbstractEpidemiological and clinical studies have suggested comorbidity between rheumatoid arthritis and Parkinson’s disease (PD), but whether there exists a causal association and the effect direction of rheumatoid arthritis on PD is controversial and elusive. To evaluate the causal relationship, we first estimated the genetic correlation between rheumatoid arthritis and PD, and then performed a two-sample Mendelian randomization analysis based on summary statistics from large genome-wide association studies of rheumatoid arthritis (N = 47,580) and PD (N = 482,703). We identified negative and significant correlation between rheumatoid arthritis and PD (genetic correlation: −0.10, P = 0.0033). Meanwhile, one standard deviation increase in rheumatoid arthritis risk was associated with a lower risk of PD (OR: 0.904, 95% CI: 0.866–0.943, P: 2.95E–06). The result was robust under all sensitivity analyses. Our results provide evidence supporting a protective role of rheumatoid arthritis on PD. A deeper understanding of the inflammation and immune response is likely to elucidate the potential pathogenesis of PD and identify therapeutic targets for PD.

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The Parkinson’s Disease Mendelian Randomization Research Portal

10.1101/604033 ◽

2019 ◽

Cited By ~ 2

Author(s):

Alastair J Noyce ◽

Sara Bandres-Ciga ◽

Jonggeol Kim ◽

Karl Heilbron ◽

Demis Kia ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

P Value ◽

Phenotypic Traits ◽

Genome Wide Association Studies ◽

Summary Statistics

ABSTRACTBackgroundMendelian randomization (MR) is a method for exploring observational associations to find evidence of causality.ObjectiveTo apply MR between multiple risk factors/phenotypic traits (exposures) and Parkinson’s disease (PD) in a large, unbiased manner, and to create a public resource for research.MethodsWe used two-sample MR in which the summary statistics relating to SNPs from genome wide association studies (GWASes) of 5,839 exposures curated on MR Base were used to assess causal relationships with PD. We selected the highest quality exposure GWASes for this report (n=401). For the disease outcome, summary statistics from the largest published PD GWAS were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted (IVW) method, followed by a range of sensitivity analyses. We used a false discovery rate (FDR) corrected p-value of <0.05 from the IVW analysis to prioritize traits of interest.ResultsWe observed evidence for causal associations between twelve exposures and risk of PD. Of these, nine were causal effects related to increasing adiposity and decreasing risk of PD. The remaining top exposures that affected PD risk were tea drinking, time spent watching television and forced vital capacity, but the latter two appeared to be biased by violations of underlying MR assumptions.DiscussionWe present a new platform which offers MR analyses for a total of 5,839 GWASes versus the largest PD GWASes available (https://pdgenetics.shinyapps.io/pdgenetics/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD.

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No Causal Association Between Adiponectin and the Risk of Rheumatoid Arthritis: A Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.670282 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hanzhu Chen ◽

Shuai Mi ◽

Jiahao Zhu ◽

Weidong Jin ◽

Yasong Li ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Genetic Correlation ◽

Causal Relationship ◽

Large Scale ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

Reverse Direction ◽

Genome Wide Association Studies

Background: Accumulating evidence from observational studies suggested that circulating adiponectin levels are associated with the risk of rheumatoid arthritis (RA), but the causality remains unknown. We aimed to assess the causal relationship of adiponectin with RA risk.Methods: Based on summary statistics from large-scale genome-wide association studies (GWAS), we quantified the genetic correlation between adiponectin and RA. Then bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship. Twenty single-nucleotide polymorphisms (SNPs) associated with adiponectin were selected as instrumental variables from a recent GWAS (n = 67,739). We applied theses SNPs to a large-scale GWAS for RA (14,361 cases and 43,923 controls) with replication using RA data from the FinnGen consortium (6,236 cases and 147,221 controls) and the UK Biobank (5,201 cases and 457,732 controls). The inverse-variance weighted (IVW) and multiple pleiotropy-robust methods were used for two-sample MR analyses.Results: Our analyses showed no significant genetic correlation between circulating adiponectin levels and RA [rG = 0.127, 95% confidence interval (CI): –0.012 to 0.266, P = 0.074]. In MR analyses, genetically predicted adiponectin levels were not significantly associated with the RA risk (odds ratio: 0.98, 95% CI: 0.88–1.09, P = 0.669). In the reverse direction analysis, there is little evidence supporting an association of genetic susceptibility to RA with adiponectin (β: 0.007, 95% CI: –0.003 to 0.018, P = 0.177). Replication analyses and sensitivity analyses using different models yielded consistent results.Conclusions: Our findings provided no evidence to support the causal effect of adiponectin levels on RA risk and of RA on circulating adiponectin levels.

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Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽

10.3390/genes12050772 ◽

2021 ◽

Vol 12 (5) ◽

pp. 772

Author(s):

João Botelho ◽

Vanessa Machado ◽

José João Mendes ◽

Paulo Mascarenhas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

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Risky behaviors and Parkinson’s disease: A Mendelian randomization study in up to 1 million study participants

10.1101/446807 ◽

2018 ◽

Cited By ~ 4

Author(s):

Sandeep Grover ◽

Greco M Fabiola Del ◽

Meike Kasten ◽

Christine Klein ◽

Christina M. Lill ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Standard Deviation ◽

Mendelian Randomization ◽

Risky Behaviors ◽

Sexual Partners ◽

P Value ◽

Genome Wide Association Studies ◽

Standard Deviation Increase ◽

Number Of Sexual Partners

AbstractObjectiveDopaminergic neurotransmission is known to be a potential modulator of risky behaviors including substance abuse, promiscuity, and gambling. Furthermore, observational studies have shown associations between risky behaviors and Parkinson’s disease; however, the causal nature of these associations remains unclear. Thus, in this study, we examine causal associations between risky behavior phenotypes on Parkinson’s disease using a Mendelian randomization approach.MethodsWe used two-sample Mendelian randomization to generate unconfounded estimates using summary statistics from two independent, large meta-analyses of genome-wide association studies on risk taking behaviors (n=370,771-939,908) and Parkinson’s disease (cases: n=9581, controls: n = 33,245). We used inverse variance weighted as the main method for judging causality.ResultsOur results support a strong protective association between the tendency to smoke and Parkinson’s disease (OR=0.714 per log odds of ever smoking; 95% CI=0.568-0.897; p-value=0.0041; Cochran Q test; p-value=0.238; I2 index=6.3%). Furthermore, we observed risk association trends between automobile speed propensity as well as the number of sexual partners and Parkinson’s disease after removal of overlapping loci with other risky traits (OR=1.986 for each standard deviation increase in normalized automobile speed propensity; 95% CI=1.215-3.243; p-value=0.0066, OR=1.635 for each standard deviation increase in number of sexual partners; 95% CI=1.165-2.293; p-value=0.0049).InterpretationThese findings provide support for a causal relationship between general risk tolerance and Parkinson’s disease and may provide new insights in the pathogenic mechanisms leading to the development of Parkinson’s disease.

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Association of genetically predicted blood sucrose with coronary heart disease and its risk factors in Mendelian randomization

Scientific Reports ◽

10.1038/s41598-020-78685-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ting Zhang ◽

Shiu Lun Au Yeung ◽

C. Mary Schooling

Keyword(s):

Risk Factors ◽

Coronary Heart Disease ◽

Heart Disease ◽

Dental Caries ◽

Multiple Testing ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Standard Deviation Increase

AbstractWe assessed the associations of genetically instrumented blood sucrose with risk of coronary heart disease (CHD) and its risk factors (i.e., type 2 diabetes, adiposity, blood pressure, lipids, and glycaemic traits), using two-sample Mendelian randomization. We used blood fructose as a validation exposure. Dental caries was a positive control outcome. We selected genetic variants strongly (P < 5 × 10–6) associated with blood sucrose or fructose as instrumental variables and applied them to summary statistics from the largest available genome-wide association studies of the outcomes. Inverse-variance weighting was used as main analysis. Sensitivity analyses included weighted median, MR-Egger and MR-PRESSO. Genetically higher blood sucrose was positively associated with the control outcome, dental caries (odds ratio [OR] 1.04 per log10 transformed effect size [median-normalized standard deviation] increase, 95% confidence interval [CI] 1.002–1.08, P = 0.04), but this association did not withstand allowing for multiple testing. The estimate for blood fructose was in the same direction. Genetically instrumented blood sucrose was not clearly associated with CHD (OR 1.01, 95% CI 0.997–1.02, P = 0.14), nor with its risk factors. Findings were similar for blood fructose. Our study found some evidence of the expected detrimental effect of sucrose on dental caries but no effect on CHD. Given a small effect on CHD cannot be excluded, further investigation with stronger genetic predictors is required.

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Unhealthy Behaviours and Risk of Parkinson’s Disease: A Mendelian Randomisation Study

Journal of Parkinson s Disease ◽

10.3233/jpd-202487 ◽

2021 ◽

pp. 1-13

Author(s):

Karl Heilbron ◽

Melanie P. Jensen ◽

Sara Bandres-Ciga ◽

Pierre Fontanillas ◽

Cornelis Blauwendraat ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protective Effect ◽

Tobacco Smoking ◽

Alcohol Intake ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Split Sample ◽

The Impact

Background: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson’s disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. Objective: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. Methods: 19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. Results: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921–0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025–1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979–0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. Conclusion: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

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Adipokines and risk of rheumatoid arthritis: a Mendelian randomization study

10.21203/rs.3.rs-36474/v1 ◽

2020 ◽

Author(s):

Jiahao Zhu ◽

Haiyan Zheng ◽

Yasong Li ◽

Tianle Wang ◽

Yaohong Zhong ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Large Scale ◽

Mendelian Randomization ◽

Association Studies ◽

Statistical Significance ◽

Sensitivity Analyses ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Primary Analysis ◽

Genome Wide

Abstract Background: Circulating adipokines levels have been reported to be associated with the risk of rheumatoid arthritis (RA). However, it is still unclear whether these associations are causal or biased by reverse causation or residual confounding. This study aimed to assess potential causal roles of five adipokines (namely, adiponectin, leptin, resistin, chemerin, and retinol-blinding protein 4 [RBP4]) in the occurrence of RA.Methods: We conducted a two-sample Mendelian randomization analysis to investigate these associations. We used summary-level data from genome-wide association studies (GWASs) for adipokines in individuals of European ancestry as the exposure, and a separate large-scale meta-analysis of a GWAS which included 14,361 RA cases and 43,923 controls of European ancestry as the outcome. Genetic variants were selected as instrumental variables if robustly genome-wide significant in their associations with adipokines. The causal effects were estimated using the inverse-variance weighted method in the primary analysis. Sensitivity analyses were performed to warrant that bias due to genetic pleiotropy was unlikely.Results: The circulating resistin was found to be the only adipokinetic factor having statistical significance, with higher levels causally associated with the risk of RA (odds ratio: 1.28; 95% confidence interval: [1.07, 1.53] per unit increase in the natural log-transformed resistin). In contrast, associations of adiponectin, leptin, chemerin, and RBP4 with risk of RA were not statistically significant. The MR assumptions did not seem to be violated. Sensitivity analyses yielded consistent findings.Conclusions: Genetically predicted circulating resistin levels were positively associated with RA risk. Our analysis suggested that resistin may play a notable causal role in RA pathogenesis. It would be beneficial for the development of clinical as well as public health strategies that target appropriate levels of resistin for future RA intervention.

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Genetic correlation and causality of cancers and Parkinson’s disease

10.1101/2020.10.07.20208124 ◽

2020 ◽

Author(s):

Konstantin Senkevich ◽

Sara Bandres-Ciga ◽

Eric Yu ◽

Upekha E. Liyanage ◽

Alastair J Noyce ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Correlation ◽

Causal Relationship ◽

Genetic Architecture ◽

Association Studies ◽

Genetic Correlations ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Shared Genetic

AbstractBackground and objectivesMost cancers appear with reduced frequency in Parkinson’s disease (PD), but the prevalence of melanoma and brain cancers are often reported to be increased. Shared genetic architecture and causal relationships to explain these associations have not been fully explored.MethodsLinkage disequilibrium score regression (LDSC) was applied for five cancer studies with available genome-wide association studies (GWAS) summary statistics to examine genetic correlations with PD. Additionally, we used GWAS summary statistics of 15 different types of cancers as exposures and two-sample Mendelian randomization to study the causal relationship with PD (outcome).ResultsLDSC analysis revealed a potential genetic correlation between PD and melanoma, breast cancer and prostate cancer. There was no evidence to support a causal relationship between the studied cancers and PD.ConclusionsOur results suggest shared genetic architecture between PD and melanoma, breast, and prostate cancers, but no obvious causal relationship between cancers and PD.

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Joint Analysis of Genetic Correlation, Mendelian Randomization and Colocalization Highlights the Bi-Directional Causal Association Between Hypothyroidism and Primary Biliary Cirrhosis

Frontiers in Genetics ◽

10.3389/fgene.2021.753352 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yanjun Wang ◽

Ping Guo ◽

Yanan Zhang ◽

Lu Liu ◽

Ran Yan ◽

...

Keyword(s):

Primary Biliary Cirrhosis ◽

Genetic Correlation ◽

Large Scale ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Joint Analysis ◽

Biliary Cirrhosis ◽

Genome Wide Association Studies ◽

Causal Association

Background: Hypothyroidism and primary biliary cirrhosis (PBC) are often co-existed in observational epidemiological studies. However, the causal relationship between them remains unclear.Methods: Genetic correlation, Mendelian randomization (MR) and colocalization analysis were combined to assess the potential causal association between hypothyroidism and PBC by using summary statistics from large-scale genome-wide association studies. Various sensitivity analyses had been conducted to assess the robustness and the consistency of the findings.Results: The linkage disequilibrium score regression demonstrated significant evidence of shared genetic architecture between hypothyroidism and PBC, with the genetic correlation estimated to be 0.117 (p = 0.006). The OR of hypothyroidism on PBC was 1.223 (95% CI, 1.072–1.396; p = 2.76 × 10−3) in MR analysis with inverse variance weighted (IVW) method. More importantly, the results from other 7MR methods with different model assumptions, were almost identical with that of IVW, suggesting the findings were robust and convincing. On the other hand, PBC was also causally associated with hypothyroidism (OR, 1.049; 95% CI, 1.010–1.089; p = 0.012), and, again, similar results can also be obtained from other MR methods. Various sensitivity analyses regarding the outlier detection and leave-one-out analysis were also performed. Besides, colocalization analysis suggested that there existed shared causal variants between hypothyroidism and PBC, further highlighting the robustness of the results.Conclusion: Our results suggest evidence for the bi-directional causal association between hypothyroidism and PBC, which may provide insights into the etiology of hypothyroidism and PBC as well as inform prevention and intervention strategies directed toward both diseases.

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