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      Does Walking Have an Association with Osteoarthritis? A Two-Sample Mendelian Randomization Analysis

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          Abstract

          Objective

          Osteoarthritis (OA) is one of the major disabling human diseases. The related studies indicate a potential correlation between walking and OA. However, there is still a lack of evidence in genetics to support the correlation between walking and OA. Therefore, this study aimed to explore the relationship between walking and OA at the genetic level.

          Methods

          The publicly available Genome Wide Association Study (GWAS) data were used, with inverse variance weighting (IVW, the random-effects model) as the main analysis method, whereas MR-Egger, Weighted median, Simple mode, and Weighted mode as the secondary analysis methods. In addition, Cochran’s Q test, pleiotropy test, and MR-Egger intercept test were conducted to examine the heterogeneity and pleiotropy of the outcome.

          Results

          In the MR analysis, IVW results showed a negative correlation between types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and OA (KOA or HOA) (odds ratio (OR) = 0.3224, 95% confidence interval (CI): 0.1261 to 0.8243), and the difference was of statistical significance (P = 0.0181). Moreover, IVW results also revealed a negative correlation between types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and KOA (OR = 0.1396, 95% CI: 0.0484 to 0.4026), and the difference was statistically significant (P = 0.0003). However, IVW results did not demonstrate any statistical significance types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and HOA (OR = 1.2075, 95% CI: 0.1978 to 7.3727, P = 0.8381).

          Conclusion

          From genetic studies, types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) is negatively correlated with knee osteoarthritis (KOA), but there is no clear evidence supporting its correlation with hip osteoarthritis (HOA).

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          Most cited references51

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          The UK Biobank resource with deep phenotyping and genomic data

          The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.
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            Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases

            Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the ‘no horizontal pleiotropy’ assumption can cause severe bias in MR. We developed the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that MR-PRESSO is best suited when horizontal pleiotropy occurs in <50% of instruments. Next, we applied MR-PRESSO, along with several other MR tests to complex traits and diseases, and found that horizontal pleiotropy: (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from −131% to 201%; (iii) induced false positive causal relationships in up to 10% of relationships; and (iv) can be corrected in some but not all instances.
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              The MR-Base platform supports systematic causal inference across the human phenome

              Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.
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                Author and article information

                Journal
                Clin Interv Aging
                Clin Interv Aging
                cia
                Clinical Interventions in Aging
                Dove
                1176-9092
                1178-1998
                31 January 2024
                2024
                : 19
                : 153-161
                Affiliations
                [1 ]Orthopedics Department, The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin, People’s Republic of China
                [2 ]Orthopedics Department, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion , Tianjin, People’s Republic of China
                [3 ]Orthopedics Department, Tianjin Jizhou District Traditional Chinese Medicine Hospital , Tianjin, People’s Republic of China
                Author notes
                Correspondence: Chao Zhang, Orthopedics Department, The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin, People’s Republic of China, Email zhangchao2004.love@163.com
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0009-0005-2753-2976
                http://orcid.org/0000-0001-5363-8575
                http://orcid.org/0000-0003-3310-3754
                Article
                442259
                10.2147/CIA.S442259
                10838505
                38312845
                8444520c-d3d3-4b13-9664-e0acabb64ca3
                © 2024 Xu et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 03 October 2023
                : 21 January 2024
                Page count
                Figures: 2, Tables: 3, References: 51, Pages: 9
                Funding
                Funded by: Tianjin Municipal Commission of Education and Science;
                This work was supported by grants from Tianjin Municipal Commission of Education and Science (2021ZD013).
                Categories
                Review

                Health & Social care
                osteoarthritis,walking,mendelian randomization
                Health & Social care
                osteoarthritis, walking, mendelian randomization

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