{"paper_id":"11947a80-9e05-453f-b399-c2eed3fa93b5","body_text":"The Causal Relationship Between Hallux Valgus and Flatfoot ：A Mendelian Randomization Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Method Article The Causal Relationship Between Hallux Valgus and Flatfoot ：A Mendelian Randomization Study Feng Liu, Ling Guo, Chun Zhang, shenghu Fan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7981614/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim: This research aimed to explore the potential causal link between hallux valgus(HV)and flatfoot. Approach: We conducted a two-sample Mendelian randomization(MR)analysis employing inverse-variance weighted(IVW)，weighted median，and MR-Egger regression methods.For the exposure variable，we utilized publicly available summary statistics from genome-wide association studies(GWAS)on HV(total n = 155，757;cases = 8，536，controls = 147，221)，while a GWAS on flatfoot(total n = 148，480;cases = 1，259，controls = 147，221)was used as the outcome measure. Findings: We identified eight single nucleotide polymorphisms(SNPs)that reached genome-wide significance from GWAS related to HV，which were utilized as instrumental variables（IVs）.The IVW method indicated a causal link between HV and flatfoot，yielding a beta coefficient of 0.410，a standard error(SE)of 0.197，and a p-value of 0.037. Conversely，MR-Egger regression suggested that directional pleiotropy was unlikely to skew the findings(intercept =-0.099，p = 0.522)，however，it did not establish a causal relationship between HV and flatfoot，presenting a beta of 1.077，SE of 1.003，and p = 0.324. Furthermore, the weighted median method indicated no causal relationship between HV and flatfoot, with a beta of 0.290, SE of 0.198, and p = 0.143. Conclusion: MR analysis suggests a potential causal link between HV and a heightened likelihood of developing flatfoot. Hallux Valgus Flatfoot mendelian randomization Figures Figure 1 Figure 2 Figure 3 1 Introduction HV and flatfoot are two common foot abnormalities. Despite extensive research into the causes of HV by specialists worldwide, a clear agreement on its origins is still lacking [ 1 ] .Generally speaking, it is known that a number of factors, including sex, genetic factors, inappropriate footwear, injuries resulting in the injury of the medial joint capsule, ligament looseness, the first metatarsal shape, excessive mobility of the first metathecuneiform joint, tightness of the achilles tendon, and different systemic conditions, are responsible for the onset of HV.Carlos Torres-Vidal [ 2 ] pointed that 90%of those who had been exposed to HV have a family history of the disease, whereas Bonney and colleagues discovered a direct link between HV and footwear decisions, according to Bonney et al [ 3 ] . Flatfoot, another common foot issue, is primarily linked to dysfunction of the posterior tibial tendon, which can manifest as tendinitis, tenosynovitis, or tears, either partial or complete. It may also result from issues with the plantar soft tissues, including neuromuscular conditions or osteoarthritis. Factors that may lead to flatfoot include genetics, injuries, changes in body weight, and congenital foot issues [ 4 ] .Nonetheless, observational studies have failed to convincingly establish a direct causal relationship between HV and flatfoot because they lack randomization, making it challenging to eliminate confounding factors and reverse causation.While randomized controlled trials are methodologically strong, they frequently encounter ethical challenges that complicate their implementation. The goal of research, according to MR, is to evaluate if there is a causal relationship between the observed association between a risk factor and an outcome by using genetic variants as instrumental variables [ 5 – 8 ] .By looking at exposure and outcome data obtained from different groups, a two-sample MR framework assesses causal effects [ 7 , 9 , 10 ] .To the best of our knowledge, there has not been any prior research employing the MR method to investigate the causal relationship between HV and the risk of flatfoot.As a result, this study aims to investigate whether HV is causally linked to the development of flatfoot through a two-sample Mendelian Randomization analysis. 2 Materials and methods 2.1Data source and genetic variant selection We performed an extensive examination of the MR Base database, available at http://www.mrbase.org/ , which is well-known for its comprehensive collection of summary statistic data from various GWAS studies. Our analysis concentrated on the publicly accessible summary statistics related to HV, which included a significant sample size of 155,757 participants, consisting of 8,536 HV cases and 147,221 controls, providing a solid foundation for investigating the link between genetic variations and the condition. To enhance our analysis, we conducted a two-sample MR study, utilizing genetic variants associated with HV as IVs to strengthen the credibility of our conclusions. We set a rigorous P-value threshold of 5.00E-08, recognized as genome-wide significant, to ensure the robustness and reliability of our results. From the relevant GWAS studies, we gathered essential summary statistics, including beta coefficients that reflect the anticipated change in the outcome variable for each unit change in the explanatory variable, along with their standard errors. This meticulous approach enabled us to concentrate on eight SNPs associated with HV (rs113536929, rs171867, rs202808, rs2140480, rs224333, rs2303597, rs72811447, rs72973328).Additionally, we enriched our analysis by utilizing the publicly available summary statistics from a GWAS on flatfoot, which included 148, 480 participants, with 1, 259 flatfoot cases and 147, 221 controls.We were able to do a lot of analysis and get important information about the relationship between HV and flatfoot by using this large dataset, which also helped to improve our knowledge of the genetic variables involved in these circumstances. 2.2 Statistical analysis for Mendelian randomization Genetic variants that are associated with a particular exposure cannot be affected by any other factor because to Mendelian randomization [ 11 , 12 ] .The main goal of our research was to determine whether SNPs and HV had an independent relationship. This preliminary evaluation was essential to confirm that the SNPs we examined were correctly related to the exposure of interest, free from confounding influences.Next, we explored the relationship between each identified SNP and the risk of developing flatfoot. This analysis involved a thorough investigation of how each SNP could potentially affect the onset of this condition, enhancing our understanding of the role genetic variations play in flatfoot prevalence. Finally, we integrated these results to establish the direct causal link between HV and flatfoot risk through MR analysis.We tried to determine the causal effect of HV on flatfoot results, which was obtained using a two-sample MR framework. This approach relied on summary statistics from separate GWASs, concentrating on eight SNPs recognized as instrumental variables in our study. By merging data from both HV and flatfoot GWASs, we were able to formulate stronger conclusions about the relationship between these two conditions. The IVW technique utilizes a meta-analytical framework to aggregate Wald ratio estimates of causal effects derived from various SNPs, yielding a reliable estimate of how the exposure influences the outcome, provided that each genetic variant meets the criteria of an IV [ 13 ] .While incorporating multiple variants in a MR analysis boosts statistical power, it also poses the risk of including pleiotropic genetic variants that may not function as valid IVs. To investigate and adjust for pleiotropy, characterized by genetic variants influencing multiple traits, the weighted median and MR-Egger regression methods were employed [ 14 ] . The MR-Egger regression analysis [ 15 ] , which is resilient against invalid instruments, evaluates and adjusts for unbalanced pleiotropy by introducing a parameter to mitigate this bias, using summary data from various individual variants. This method conducts a weighted linear regression of gene-outcome coefficients against gene-exposure coefficients, where the slope indicates the causal effect estimate, and the intercept reflects the average horizontal pleiotropic effect across the genetic variants [ 16 ] . The weighted median estimator provides a consistent causal effect estimate, even if up to 50%of the data stems from invalid IVs [ 16 , 17 ] . In comparison to MR-Egger analysis, the weighted median estimator offers enhanced precision in its estimates. Statistical significance was determined at P < 0.05 [ 18 , 19 ] . All MR analyses were performed using the MR Base platform(App version: 1.4.3 8a77eb(25 October 2020), R version: 4.0.3) [ 20 ] . 2.3 Sensitivity test We utilized the leave-one-out approach to evaluate the sensitivity of the findings. This involved systematically excluding each SNP individually and then evaluating the impact of the remaining SNPs using the IVW method [ 21 ] . Through this process, we analyzed how each SNP influenced the causal inference. 3 Results 3.1.Instrumental variables for Mendelian randomization We identified eight distinct SNPs from GWASs linked to HV to act as IVs.Each of these SNPs shows a notable correlation with HV throughout the genome. Among these eight, we found a total of eight connections to flatfoot; however, none of these reached statistical significance.According to the R value, the genetic variations that were chosen as IVs accounted for 1.4%of the variation in the exposure.The P-value of each individual variation is 5.00E-08, which corresponds to a F statistic greater than 30.A threshold of F < 10 is employed to identify weak instruments, indicating that the likelihood of weak instrument bias is minimal. 3.2Mendelian randomization results The IVW approach yielded compelling evidence that hints at a causal link between HV and flatfoot. As shown in Table 1 and Fig. 1 , as shown in Figs. 1 and 2 , the analysis showed a beta coefficient of 0.410, a standard error of 0.197, and a p-value of 0.037. This suggests a significant correlation, indicating that HV could elevate the risk of developing flatfoot.The average pleiotropic effect of the examined genetic variations is also represented by the intercept value;this is one of the most important measurements.In this circumstance, a non-zero intercept detected by the MR-Egger test indicates the presence of directional pleiotropy.Nonetheless, the MR-Egger regression analysis yielded an intercept of-0.099 and a p-value of 0.522, indicating a low likelihood of directional pleiotropy influencing the results.Upon analysis with the MR-Egger method, no causal relationship between HV and flatfoot was identified, as evidenced by a beta of 1.077, a standard error of 1.003, and a p-value of 0.324(see Table 1 and Figs. 1 and 2 ).Furthermore, the weighted median method reinforced the absence of a causal relationship, yielding a beta of 0.290, a standard error of 0.198, and a p-value of 0.143(Table 1 and Figs. 2 ).In summary, while the IVW method suggests a possible causal effect of HV on flatfoot development, both the MR-Egger and weighted median methods indicate no causal connection. The variation in outcomes among these methods calls for careful consideration, as the MR analysis findings may still suggest a conceivable causal relationship between HV and flatfoot. Table 1 presents the MR estimates derived from various approaches used to evaluate the causal impact of HV on the likelihood of developing flatfoot. MR method Number of SNPs Beta SE 95% confidence interval OR P-value MR-Egger 8 1.077 1.003 0.411–20.966 2.936 0.324 Weighted median 8 0.290 0.198 0.906–1.972 1.337 0.143 Inverse -variance weighted 8 0.4102 0.197 1.025–2.216 1.507 0.037 3.3 Sensitivity test According to the results, genetic pleiotropy had no effect on the result(MR-Egger regression intercept=-0.099, SE = 0.15, P = 0.522).Moreover, no one SNP was significant in the causal assessment(Fig. 3 );the Leave-one-out analysis showed that this was not the case in Fig. 3 . 4 Discussion A lot of discussion has been brought about by the connection between HV and flatfoot. Various viewpoints have emerged regarding their connection: 1) Some researchers assert that HV and flatfoot are not causally linked. A study by Saragas et al [ 22 ] involving 110 women in an urban U.S. setting found no notable differences in flatfoot occurrence, first metatarsal length, or sesamoid bone positioning between those with and without HV. Coughlin et al [ 23 ] further indicated that the severity of HV does not correlate with flatfoot, gastrocnemius tightness, or first ray stability. A retrospective analysis by Korean researcher Dong Hun Suh [ 24 ] on 122 adult males with HV concluded that there was no significant link between flatfoot and HV severity, recurrence, radiographic findings, or clinical assessments. They observed no meaningful association between flatfoot and the radiographic indicators of HV severity, clinical outcomes, or preoperative deformity. 2) Alternatively, HV might predispose individuals to flatfoot, as King [ 25 ] suggested that prolonged HV can alter arch height, potentially leading to flatfoot. 3) On the other side, flatfoot could also raise the possibility of getting HV. Smyth [ 26 ] and colleagues noted that forefoot deformities often arise from midfoot biomechanical issues, while Daisuke, et al [ 27 ] found that individuals with flatfoot are more likely to develop HV, with incidence rates between 36.1% and 48%. Shibuya et al [ 28 ] studied 94 patients and found a significant relationship between flatfoot deformity and hallux valgus angle(HVA)deformity. Turkish researcher Zafer Atbaşi and his team [ 29 ] , in a study of 213 adult males, provided compelling evidence of a strong link between flatfoot and HV. González-Martín et al [ 30 ] noted in clinical studies that individuals with HV often show a collapse of the medial longitudinal arch, suggesting a causal connection. Blackwood et al [ 31 ] examined patients with both conditions and found that arch collapse may predispose individuals to HV. 4) Lastly, a shared underlying cause may exist for both HV and flatfoot. Lee et al [ 32 ] conducted weight-bearing imaging studies on HV progression, revealing a higher incidence of instability in the first metatarsocuneiform joint among patients with both HV and flatfoot. Perera AM [ 33 ] posited that the first metatarsal, a key structure in HV deformity, is also vital for sustaining the medial longitudinal arch, and alterations in this area can lead to arch collapse, which is similarly observed in flatfoot. MR reduces the biases typical of observational research [ 34 , 35 ] .Nevertheless, pleiotropy, which happens when genetic polymorphisms affect several characteristics, can have an impact on MR investigations. This connection between genetic variants and various phenotypes can distort MR estimates and lead to biased causal interpretations.While analyzing several variants in MR can increase the likelihood of include pleiotropic variants that do not function as valid IVs, it also increases the likelihood of including them that do so in MR. Consequently, it is essential to implement sensitivity analyses to validate the findings from MR studies.To address the issue of pleiotropy [ 36 ] , we utilized a weighted median estimator and conducted MR-Egger regression toassess unbalanced pleiotropy and obtain a causal estimate of the exposure's effect on the outcome. Our findings varied across the three methods employed.The MR-Egger method led to a reduction in both precision and power, while the weighted median estimator yielded results that differed from those of the IVW estimator, thereby enhancing confidence in these relationships. Our findings support earlier research that suggests a link between HV and flatfoot, potentially shedding light on the mechanisms by which HV influences flatfoot risk. The purpose of this paper is to identify some limitations which are to be considered in the results evaluation. Firstly, it is essential to understand that genetic variations have a limited impact on HV, likely explaining only a small portion of the variance seen in this condition [ 37 ] . This limitation indicates that our study's analytical capacity may not have been adequate to identify a significant correlation. Secondly, the categorization of individuals with HV and flatfoot relied on non-cancer illness codes based on self-reported information. This approach raises the potential for biases, such as selection and information bias, which could ultimately compromise the reliability of our findings. Thirdly, existing research on the link between HV and flatfoot mainly involves participants from particular ancestral groups. Since the underlying causes may differ across ethnicities and the risk of selection bias is present, there is a pressing need for additional MR studies to investigate these relationships in varied populations. Fourthly, demographic variables like sex and age affect HV prevalence, with male-to-female ratios reported between 1:9 and 1:15.Specifically, prevalence rates at ages 7 and 13 are 36.91%and 29%, respectively. Lastly, our study incorporated an MR analysis using a second cohort of publicly available single SNP data from patients diagnosed with flatfoot, utilizing instruments from the HV study.However, to our knowledge, this research marks the first attempt to apply MR methodology to investigate the causal link between HV and flatfoot. To sum up, the results from the Mendelian Randomization study suggest that HV might play a direct role in increasing the likelihood of flatfoot development. This implies that HV could be an important factor in the emergence of flatfoot among people. While the exact processes that link HV to flatfoot are not fully understood, it is clear that more research is needed to clarify this connection. Further investigations are essential to delve into the intricacies of this relationship and to shed light on the causes related to flatfoot arising from HV. Declarations Compliance with Ethical Guidelines The authors did not perform any research involving human subjects or animals in this article. Conflicts of interest To declare, the writers do not have any financial or nonfinancial conflicts of interest. Author Contribution The concept of the manuscript was devised by Feng Liu and Shenghu Fan.Ling Guo and Chun Zhang performed the overall literature searches and were in charge of writing. All authors discussed the content of the article and gave suggestions. References MIN JJ, KWON S S, SUNG K H et al. Progression of planovalgus deformity in patients with cerebral palsy [J]. BMC Musculoskelet Disord, 2020, 21(1). PIQUé-VIDAL C, SOLé MT. Hallux valgus inheritance: pedigree research in 350 patients with bunion deformity [J]. J Foot Ankle Surg. 2007;46(3):149–54. BONNEY G, MACNAB I. Hallux valgus and hallux rigidus; a critical survey of operative results [J]. J bone joint Surg Br volume. 1952;3:34–B. PINNEY S J, LIN S S. 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06:43:36\",\"extension\":\"png\",\"order_by\":8,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":20890,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Onlinefloatimage3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7981614/v1/de175e8c36d35efd1a0ef936.png\"},{\"id\":95228220,\"identity\":\"738cd199-a229-4fea-9d65-663b08495959\",\"added_by\":\"auto\",\"created_at\":\"2025-11-05 16:33:28\",\"extension\":\"xml\",\"order_by\":9,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":63489,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"6f68e7d9421a45899cdae1c0f9fa485e1structuring.xml\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7981614/v1/1ad89fbccf638cc788fe9573.xml\"},{\"id\":95173467,\"identity\":\"ab744e48-ed09-4768-ac87-084983c97ce6\",\"added_by\":\"auto\",\"created_at\":\"2025-11-05 06:43:36\",\"extension\":\"html\",\"order_by\":10,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":70925,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"earlyproof.html\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7981614/v1/49b59931b154c243392d6ddb.html\"},{\"id\":95173457,\"identity\":\"20ab3bd2-93ba-471a-b490-c93ea9c80f48\",\"added_by\":\"auto\",\"created_at\":\"2025-11-05 06:43:36\",\"extension\":\"jpeg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":42376,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003edisplays a forest plot illustrating the causal impacts of single nucleotide polymorphisms linked to HV in relation to flatfoot. The red lines indicate the significance of the results obtained from the MR-Egger test and the IVW method.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage1.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7981614/v1/3710ee5cafb2f7a03308438e.jpeg\"},{\"id\":95173462,\"identity\":\"447dcd5e-1898-4950-abdc-ef1bd203449f\",\"added_by\":\"auto\",\"created_at\":\"2025-11-05 06:43:36\",\"extension\":\"jpeg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":75228,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eillustrates a scatter plot depicting the relationship between SNPs linked to HV and the likelihood of developing flatfoot.The graph shows the effect sizes for the SNP-HV correlation on the x-axis(in standard deviationunits)and the SNP-flatfoot correlation on the y-axis(in log odds ratio)，accompanied by 95%confidence intervals. The slopes of the regression lines represent causal estimates derived from three Mendelian randomization techniques:the IVW method，the weighted median estimator, and MR-Egger.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage2.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7981614/v1/e9e40a6eaf5f565d83c6d8ec.jpeg\"},{\"id\":95227846,\"identity\":\"ee54968b-c650-4b94-85ef-83394a9ae44e\",\"added_by\":\"auto\",\"created_at\":\"2025-11-05 16:33:01\",\"extension\":\"jpeg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":43460,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eshows the correlation of SNPs associated with flatfoot risk with the leave-one-out analysis of HV. Each black dot signifies the outcome of the IVW MR approach used to determine the causal influence of HV on flatfoot while omitting a specific SNP from the evaluation.On the other hand，all SNPs are included in the IVW estimate shown by each red dot.This sensitivity analysis indicates that no individual SNP significantly influences the overall relationship between HV and flatfoot.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage3.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7981614/v1/e359e1ceb5b14b69a4e3b78f.jpeg\"},{\"id\":95312206,\"identity\":\"9c38d344-0216-419f-808e-65644d743642\",\"added_by\":\"auto\",\"created_at\":\"2025-11-06 15:48:07\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":660499,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7981614/v1/d44457fb-0b99-4ce8-9e1e-39612fb646d7.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"The Causal Relationship Between Hallux Valgus and Flatfoot ：A Mendelian Randomization Study\",\"fulltext\":[{\"header\":\"1 Introduction\",\"content\":\"\\u003cp\\u003eHV and flatfoot are two common foot abnormalities. Despite extensive research into the causes of HV by specialists worldwide, a clear agreement on its origins is still lacking\\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]\\u003c/sup\\u003e.Generally speaking, it is known that a number of factors, including sex, genetic factors, inappropriate footwear, injuries resulting in the injury of the medial joint capsule, ligament looseness, the first metatarsal shape, excessive mobility of the first metathecuneiform joint, tightness of the achilles tendon, and different systemic conditions, are responsible for the onset of HV.Carlos Torres-Vidal\\u003csup\\u003e[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]\\u003c/sup\\u003e pointed that 90%of those who had been exposed to HV have a family history of the disease, whereas Bonney and colleagues discovered a direct link between HV and footwear decisions, according to Bonney et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]\\u003c/sup\\u003e. Flatfoot, another common foot issue, is primarily linked to dysfunction of the posterior tibial tendon, which can manifest as tendinitis, tenosynovitis, or tears, either partial or complete. It may also result from issues with the plantar soft tissues, including neuromuscular conditions or osteoarthritis. Factors that may lead to flatfoot include genetics, injuries, changes in body weight, and congenital foot issues\\u003csup\\u003e[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]\\u003c/sup\\u003e.Nonetheless, observational studies have failed to convincingly establish a direct causal relationship between HV and flatfoot because they lack randomization, making it challenging to eliminate confounding factors and reverse causation.While randomized controlled trials are methodologically strong, they frequently encounter ethical challenges that complicate their implementation.\\u003c/p\\u003e\\u003cp\\u003eThe goal of research, according to MR, is to evaluate if there is a causal relationship between the observed association between a risk factor and an outcome by using genetic variants as instrumental variables\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR6 CR7\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]\\u003c/sup\\u003e.By looking at exposure and outcome data obtained from different groups, a two-sample MR framework assesses causal effects\\u003csup\\u003e[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e.To the best of our knowledge, there has not been any prior research employing the MR method to investigate the causal relationship between HV and the risk of flatfoot.As a result, this study aims to investigate whether HV is causally linked to the development of flatfoot through a two-sample Mendelian Randomization analysis.\\u003c/p\\u003e\"},{\"header\":\"2 Materials and methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.1Data source and genetic variant selection\\u003c/h2\\u003e\\u003cp\\u003eWe performed an extensive examination of the MR Base database, available at \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://www.mrbase.org/\\u003c/span\\u003e\\u003cspan address=\\\"http://www.mrbase.org/\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e, which is well-known for its comprehensive collection of summary statistic data from various GWAS studies. Our analysis concentrated on the publicly accessible summary statistics related to HV, which included a significant sample size of 155,757 participants, consisting of 8,536 HV cases and 147,221 controls, providing a solid foundation for investigating the link between genetic variations and the condition. To enhance our analysis, we conducted a two-sample MR study, utilizing genetic variants associated with HV as IVs to strengthen the credibility of our conclusions. We set a rigorous P-value threshold of 5.00E-08, recognized as genome-wide significant, to ensure the robustness and reliability of our results. From the relevant GWAS studies, we gathered essential summary statistics, including beta coefficients that reflect the anticipated change in the outcome variable for each unit change in the explanatory variable, along with their standard errors. This meticulous approach enabled us to concentrate on eight SNPs associated with HV (rs113536929, rs171867, rs202808, rs2140480, rs224333, rs2303597, rs72811447, rs72973328).Additionally, we enriched our analysis by utilizing the publicly available summary statistics from a GWAS on flatfoot, which included 148, 480 participants, with 1, 259 flatfoot cases and 147, 221 controls.We were able to do a lot of analysis and get important information about the relationship between HV and flatfoot by using this large dataset, which also helped to improve our knowledge of the genetic variables involved in these circumstances.\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.2 Statistical analysis for Mendelian randomization\\u003c/h2\\u003e\\u003cp\\u003eGenetic variants that are associated with a particular exposure cannot be affected by any other factor because to Mendelian randomization\\u003csup\\u003e[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]\\u003c/sup\\u003e.The main goal of our research was to determine whether SNPs and HV had an independent relationship. This preliminary evaluation was essential to confirm that the SNPs we examined were correctly related to the exposure of interest, free from confounding influences.Next, we explored the relationship between each identified SNP and the risk of developing flatfoot. This analysis involved a thorough investigation of how each SNP could potentially affect the onset of this condition, enhancing our understanding of the role genetic variations play in flatfoot prevalence. Finally, we integrated these results to establish the direct causal link between HV and flatfoot risk through MR analysis.We tried to determine the causal effect of HV on flatfoot results, which was obtained using a two-sample MR framework. This approach relied on summary statistics from separate GWASs, concentrating on eight SNPs recognized as instrumental variables in our study. By merging data from both HV and flatfoot GWASs, we were able to formulate stronger conclusions about the relationship between these two conditions.\\u003c/p\\u003e\\u003cp\\u003eThe IVW technique utilizes a meta-analytical framework to aggregate Wald ratio estimates of causal effects derived from various SNPs, yielding a reliable estimate of how the exposure influences the outcome, provided that each genetic variant meets the criteria of an IV\\u003csup\\u003e[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]\\u003c/sup\\u003e.While incorporating multiple variants in a MR analysis boosts statistical power, it also poses the risk of including pleiotropic genetic variants that may not function as valid IVs. To investigate and adjust for pleiotropy, characterized by genetic variants influencing multiple traits, the weighted median and MR-Egger regression methods were employed\\u003csup\\u003e[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]\\u003c/sup\\u003e. The MR-Egger regression analysis\\u003csup\\u003e[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]\\u003c/sup\\u003e, which is resilient against invalid instruments, evaluates and adjusts for unbalanced pleiotropy by introducing a parameter to mitigate this bias, using summary data from various individual variants. This method conducts a weighted linear regression of gene-outcome coefficients against gene-exposure coefficients, where the slope indicates the causal effect estimate, and the intercept reflects the average horizontal pleiotropic effect across the genetic variants\\u003csup\\u003e[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]\\u003c/sup\\u003e. The weighted median estimator provides a consistent causal effect estimate, even if up to 50%of the data stems from invalid IVs\\u003csup\\u003e[\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]\\u003c/sup\\u003e. In comparison to MR-Egger analysis, the weighted median estimator offers enhanced precision in its estimates. Statistical significance was determined at P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05\\u003csup\\u003e[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]\\u003c/sup\\u003e. All MR analyses were performed using the MR Base platform(App version: 1.4.3 8a77eb(25 October 2020), R version: 4.0.3)\\u003csup\\u003e[\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e2.3 Sensitivity test\\u003c/h2\\u003e\\u003cp\\u003eWe utilized the leave-one-out approach to evaluate the sensitivity of the findings. This involved systematically excluding each SNP individually and then evaluating the impact of the remaining SNPs using the IVW method\\u003csup\\u003e[\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]\\u003c/sup\\u003e. Through this process, we analyzed how each SNP influenced the causal inference.\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"3 Results\",\"content\":\"\\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e3.1.Instrumental variables for Mendelian randomization\\u003c/h2\\u003e\\u003cp\\u003eWe identified eight distinct SNPs from GWASs linked to HV to act as IVs.Each of these SNPs shows a notable correlation with HV throughout the genome. Among these eight, we found a total of eight connections to flatfoot; however, none of these reached statistical significance.According to the R value, the genetic variations that were chosen as IVs accounted for 1.4%of the variation in the exposure.The P-value of each individual variation is 5.00E-08, which corresponds to a F statistic greater than 30.A threshold of F\\u0026thinsp;\\u0026lt;\\u0026thinsp;10 is employed to identify weak instruments, indicating that the likelihood of weak instrument bias is minimal.\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e3.2Mendelian randomization results\\u003c/h2\\u003e\\u003cp\\u003eThe IVW approach yielded compelling evidence that hints at a causal link between HV and flatfoot. As shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e and Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e, as shown in Figs.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e and \\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e, the analysis showed a beta coefficient of 0.410, a standard error of 0.197, and a p-value of 0.037. This suggests a significant correlation, indicating that HV could elevate the risk of developing flatfoot.The average pleiotropic effect of the examined genetic variations is also represented by the intercept value;this is one of the most important measurements.In this circumstance, a non-zero intercept detected by the MR-Egger test indicates the presence of directional pleiotropy.Nonetheless, the MR-Egger regression analysis yielded an intercept of-0.099 and a p-value of 0.522, indicating a low likelihood of directional pleiotropy influencing the results.Upon analysis with the MR-Egger method, no causal relationship between HV and flatfoot was identified, as evidenced by a beta of 1.077, a standard error of 1.003, and a p-value of 0.324(see Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e and Figs.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e and \\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).Furthermore, the weighted median method reinforced the absence of a causal relationship, yielding a beta of 0.290, a standard error of 0.198, and a p-value of 0.143(Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e and Figs.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).In summary, while the IVW method suggests a possible causal effect of HV on flatfoot development, both the MR-Egger and weighted median methods indicate no causal connection. The variation in outcomes among these methods calls for careful consideration, as the MR analysis findings may still suggest a conceivable causal relationship between HV and flatfoot.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003epresents the MR estimates derived from various approaches used to evaluate the causal impact of HV on the likelihood of developing flatfoot.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"7\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMR method\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eNumber of\\u003c/p\\u003e\\u003cp\\u003eSNPs\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eBeta\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eSE\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e95% confidence\\u003c/p\\u003e\\u003cp\\u003einterval\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eOR\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eP-value\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMR-Egger\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1.077\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e1.003\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0.411\\u0026ndash;20.966\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e2.936\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.324\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eWeighted median\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0.290\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e0.198\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0.906\\u0026ndash;1.972\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e1.337\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.143\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eInverse -variance weighted\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0.4102\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e0.197\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1.025\\u0026ndash;2.216\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e1.507\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.037\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003e3.3 Sensitivity test\\u003c/h2\\u003e\\u003cp\\u003eAccording to the results, genetic pleiotropy had no effect on the result(MR-Egger regression intercept=-0.099, SE\\u0026thinsp;=\\u0026thinsp;0.15, P\\u0026thinsp;=\\u0026thinsp;0.522).Moreover, no one SNP was significant in the causal assessment(Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e);the Leave-one-out analysis showed that this was not the case in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"4 Discussion\",\"content\":\"\\u003cp\\u003eA lot of discussion has been brought about by the connection between HV and flatfoot. Various viewpoints have emerged regarding their connection: 1) Some researchers assert that HV and flatfoot are not causally linked. A study by Saragas et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]\\u003c/sup\\u003e involving 110 women in an urban U.S. setting found no notable differences in flatfoot occurrence, first metatarsal length, or sesamoid bone positioning between those with and without HV. Coughlin et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]\\u003c/sup\\u003e further indicated that the severity of HV does not correlate with flatfoot, gastrocnemius tightness, or first ray stability. A retrospective analysis by Korean researcher Dong Hun Suh\\u003csup\\u003e[\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]\\u003c/sup\\u003e on 122 adult males with HV concluded that there was no significant link between flatfoot and HV severity, recurrence, radiographic findings, or clinical assessments. They observed no meaningful association between flatfoot and the radiographic indicators of HV severity, clinical outcomes, or preoperative deformity. 2) Alternatively, HV might predispose individuals to flatfoot, as King\\u003csup\\u003e[\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]\\u003c/sup\\u003e suggested that prolonged HV can alter arch height, potentially leading to flatfoot. 3) On the other side, flatfoot could also raise the possibility of getting HV. Smyth\\u003csup\\u003e[\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]\\u003c/sup\\u003e and colleagues noted that forefoot deformities often arise from midfoot biomechanical issues, while Daisuke, et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]\\u003c/sup\\u003e found that individuals with flatfoot are more likely to develop HV, with incidence rates between 36.1% and 48%. Shibuya et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]\\u003c/sup\\u003e studied 94 patients and found a significant relationship between flatfoot deformity and hallux valgus angle(HVA)deformity. Turkish researcher Zafer Atbaşi and his team\\u003csup\\u003e[\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]\\u003c/sup\\u003e, in a study of 213 adult males, provided compelling evidence of a strong link between flatfoot and HV. Gonz\\u0026aacute;lez-Mart\\u0026iacute;n et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]\\u003c/sup\\u003e noted in clinical studies that individuals with HV often show a collapse of the medial longitudinal arch, suggesting a causal connection. Blackwood et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]\\u003c/sup\\u003e examined patients with both conditions and found that arch collapse may predispose individuals to HV. 4) Lastly, a shared underlying cause may exist for both HV and flatfoot. Lee et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]\\u003c/sup\\u003e conducted weight-bearing imaging studies on HV progression, revealing a higher incidence of instability in the first metatarsocuneiform joint among patients with both HV and flatfoot. Perera AM\\u003csup\\u003e[\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e]\\u003c/sup\\u003e posited that the first metatarsal, a key structure in HV deformity, is also vital for sustaining the medial longitudinal arch, and alterations in this area can lead to arch collapse, which is similarly observed in flatfoot.\\u003c/p\\u003e\\u003cp\\u003eMR reduces the biases typical of observational research\\u003csup\\u003e[\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e]\\u003c/sup\\u003e.Nevertheless, pleiotropy, which happens when genetic polymorphisms affect several characteristics, can have an impact on MR investigations. This connection between genetic variants and various phenotypes can distort MR estimates and lead to biased causal interpretations.While analyzing several variants in MR can increase the likelihood of include pleiotropic variants that do not function as valid IVs, it also increases the likelihood of including them that do so in MR. Consequently, it is essential to implement sensitivity analyses to validate the findings from MR studies.To address the issue of pleiotropy\\u003csup\\u003e[\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e]\\u003c/sup\\u003e, we utilized a weighted median estimator and conducted MR-Egger regression toassess unbalanced pleiotropy and obtain a causal estimate of the exposure's effect on the outcome. Our findings varied across the three methods employed.The MR-Egger method led to a reduction in both precision and power, while the weighted median estimator yielded results that differed from those of the IVW estimator, thereby enhancing confidence in these relationships. Our findings support earlier research that suggests a link between HV and flatfoot, potentially shedding light on the mechanisms by which HV influences flatfoot risk.\\u003c/p\\u003e\\u003cp\\u003eThe purpose of this paper is to identify some limitations which are to be considered in the results evaluation. Firstly, it is essential to understand that genetic variations have a limited impact on HV, likely explaining only a small portion of the variance seen in this condition\\u003csup\\u003e[\\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e]\\u003c/sup\\u003e. This limitation indicates that our study's analytical capacity may not have been adequate to identify a significant correlation. Secondly, the categorization of individuals with HV and flatfoot relied on non-cancer illness codes based on self-reported information. This approach raises the potential for biases, such as selection and information bias, which could ultimately compromise the reliability of our findings. Thirdly, existing research on the link between HV and flatfoot mainly involves participants from particular ancestral groups. Since the underlying causes may differ across ethnicities and the risk of selection bias is present, there is a pressing need for additional MR studies to investigate these relationships in varied populations. Fourthly, demographic variables like sex and age affect HV prevalence, with male-to-female ratios reported between 1:9 and 1:15.Specifically, prevalence rates at ages 7 and 13 are 36.91%and 29%, respectively. Lastly, our study incorporated an MR analysis using a second cohort of publicly available single SNP data from patients diagnosed with flatfoot, utilizing instruments from the HV study.However, to our knowledge, this research marks the first attempt to apply MR methodology to investigate the causal link between HV and flatfoot.\\u003c/p\\u003e\\u003cp\\u003eTo sum up, the results from the Mendelian Randomization study suggest that HV might play a direct role in increasing the likelihood of flatfoot development. This implies that HV could be an important factor in the emergence of flatfoot among people. While the exact processes that link HV to flatfoot are not fully understood, it is clear that more research is needed to clarify this connection. Further investigations are essential to delve into the intricacies of this relationship and to shed light on the causes related to flatfoot arising from HV.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003ch2\\u003eCompliance with Ethical Guidelines\\u003c/h2\\u003e\\u003cp\\u003eThe authors did not perform any research involving human subjects or animals in this article.\\u003c/p\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eConflicts of interest\\u003c/strong\\u003e\\u003cp\\u003eTo declare, the writers do not have any financial or nonfinancial conflicts of interest.\\u003c/p\\u003e\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eThe concept of the manuscript was devised by Feng Liu and Shenghu Fan.Ling Guo and Chun Zhang performed the overall literature searches and were in charge of writing. All authors discussed the content of the article and gave suggestions.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eMIN JJ, KWON S S, SUNG K H et al. Progression of planovalgus deformity in patients with cerebral palsy [J]. BMC Musculoskelet Disord, 2020, 21(1).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePIQU\\u0026eacute;-VIDAL C, SOL\\u0026eacute; MT. Hallux valgus inheritance: pedigree research in 350 patients with bunion deformity [J]. J Foot Ankle Surg. 2007;46(3):149\\u0026ndash;54.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBONNEY G, MACNAB I. Hallux valgus and hallux rigidus; a critical survey of operative results [J]. J bone joint Surg Br volume. 1952;3:34\\u0026ndash;B.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePINNEY S J, LIN S S. Current Concept Review. Acquired Adult Flatfoot Deformity [J]. Volume 27. Foot \\u0026amp; Ankle International; 2006. pp. 66\\u0026ndash;75. 1.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSTEPHEN B, DANIEL R M, BUTTERWORTH AS et al. Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways [J]. Int J Epidemiol, 2015, 44(2).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBAE SC, LEE Y H. Causal association between body mass index and risk of rheumatoid arthritis: A Mendelian randomization study [J]. Eur J Clin Invest. 2019;49(4):e13076.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eTANG M. CHEN L. Mendelian randomization in cancer research: opportunities and challenges [J]. Volume 20. Infectious Agents \\u0026amp; Cancer; 2025. 1.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eZHAO P, CHEN Z, WEN Y, et al. 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The Journal of Foot and Ankle Surgery; 2020.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eKING D M, TOOLAN BC. Associated deformities and hypermobility in hallux valgus: an investigation with weightbearing radiographs [J]. Volume 25. Foot \\u0026amp; Ankle International; 2004. pp. 251\\u0026ndash;5. 4.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSMYTH N A, AIYER A A, KAPLAN J R, et al. Adult-acquired flatfoot deformity [J]. Eur J Orthop Surg Traumatol. 2017;27(4):1\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eDAISUKE URITANI. TAKAHIKO, et al. Associations between toe grip strength and hallux valgus, toe curl ability, and foot arch height in Japanese adults aged 20 to 79 years: a cross-sectional study [J]. Journal of Foot \\u0026amp; Ankle Research; 2015.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eNAOHIRO S, JACOB J, BLAKE P et al. 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Rheumatology International; 2017.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBLACKWOOD S. GOSSETT L. Hallux Valgus/Medial Column Instability and Their Relationship with Posterior Tibial Tendon Dysfunction [J]. Volume 23. Foot \\u0026amp; Ankle Clinics; 2018. pp. 297\\u0026ndash;313. 2.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSEUNG YEOL, LEE, et al. Radiographic Measurements Associated With the Natural Progression of the Hallux Valgus During at Least 2 Years of Follow-up [J]. Foot Ankle Int. 2018;39(4):463\\u0026ndash;70.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePERERA AM. The Pathogenesis of Hallux Valgus [J]. J Bone Joint Surg Am Volume. 2011;93(17):1650\\u0026ndash;61.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSMITH GD, Davey Smith EBRAHIMS, Ebrahim G. S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 33, 30\\u0026ndash;42 [J]. International Journal of Epidemiology, 2004, 33(1): 30\\u0026ndash;42.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSMITH G, Mendelian Randomization EBRAHIMS. Genetic Variants as Instruments for Strengthening Causal Inference in Observational Studies [J]. 2008.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePAABY A B, ROCKMAN MV. The many faces of pleiotropy [J]. Trends Genet Tig. 2013;29(2):66\\u0026ndash;73.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSWERDLOW D I, KUCHENBAECKER, KB et al. mendelian randomization selecting instruments for mendelian randomization in the wake of genome-wide association studies [J]. 2019.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Hallux Valgus, Flatfoot, mendelian randomization\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7981614/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7981614/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eAim: \\u003c/strong\\u003eThis research aimed to explore the potential causal link between hallux valgus(HV)and flatfoot.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eApproach:\\u003c/strong\\u003e We conducted a two-sample Mendelian randomization(MR)analysis employing inverse-variance weighted(IVW)，weighted median，and MR-Egger regression methods.For the exposure variable，we utilized publicly available summary statistics from genome-wide association studies(GWAS)on HV(total n = 155，757;cases = 8，536，controls = 147，221)，while a GWAS on flatfoot(total n = 148，480;cases = 1，259，controls = 147，221)was used as the outcome measure.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFindings: \\u003c/strong\\u003eWe identified eight single nucleotide polymorphisms(SNPs)that reached genome-wide significance from GWAS related to HV，which were utilized as instrumental variables（IVs）.The IVW method indicated a causal link between HV and flatfoot，yielding a beta coefficient of 0.410，a standard error(SE)of 0.197，and a p-value of 0.037. Conversely，MR-Egger regression suggested that directional pleiotropy was unlikely to skew the findings(intercept =-0.099，p = 0.522)，however，it did not establish a causal relationship between HV and flatfoot，presenting a beta of 1.077，SE of 1.003，and p = 0.324. Furthermore, the weighted median method indicated no causal relationship between HV and flatfoot, with a beta of 0.290, SE of 0.198, and p = 0.143.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusion:\\u003c/strong\\u003e MR analysis suggests a potential causal link between HV and a heightened likelihood of developing flatfoot.\\u003c/p\\u003e\",\"manuscriptTitle\":\"The Causal Relationship Between Hallux Valgus and Flatfoot ：A Mendelian Randomization Study\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-11-05 06:43:32\",\"doi\":\"10.21203/rs.3.rs-7981614/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"ea24d220-7245-46c9-906a-71f32da7673f\",\"owner\":[],\"postedDate\":\"November 5th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-11-05T10:09:02+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-11-05 06:43:32\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7981614\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7981614\",\"identity\":\"rs-7981614\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}