Hallux valgus, one of the most common structural foot deformities, is characterized by abduction of the great toe (hallux) with respect to the first metatarsal joint [1
]. Hallux valgus is associated with pain, functional limitation, increased risk for falls, and diminished quality of life [2
]. The condition is multifactorial in origin and the etiology is not completely understood. Hallux valgus is associated with female sex, older age, lower body mass index (BMI), and certain footwear types [1
]. Structural factors, such as metatarsal length and head shape, first ray hypermobility, and hind-foot pronation, are also considered to be important in hallux valgus development [6
]. Hallux valgus is heritable, with estimates ranging from 0.29 to 0.89, suggesting that genetics may influence the development of this deformity [8
]. Identifying genetic variants associated with hallux valgus using an agnostic genome-wide approach may provide insights into the development of hallux valgus and lead to new treatment strategies.
The first and only genome-wide association study (GWAS) of hallux valgus was conducted as a meta-analysis in 4409 Caucasians based on a combined analysis of the Framingham Heart Study (FHS), the Genetics of Generalized Osteoarthritis (GOGO) Study, and the Johnston County Osteoarthritis Project (JoCoOA) [10
]. This study did not find genome-wide significant associations with hallux valgus in either gender-specific or sex-combined GWAS meta-analyses. In this report, we expand the prior genome-wide association analysis by including association results from the Osteoarthritis Initiative (OAI), in which hallux valgus has also been measured and genome-wide genotyping is available.
The objective of the present paper is to identify novel genetic variants associated with hallux valgus in this expanded sample and with deeper genotype imputation performed (i.e., from 1000 Genomes to the Haplotype Reference Consortium (HRC) reference panel). With the addition of the OAI, the GWA sample size increased to 5925 Caucasian participants, representing a 34% increase in size from the prior GWA sample of 4409 subjects.
In the expanded hallux valgus meta-analysis on individuals of European ancestry, we identified a novel locus for hallux valgus in CLCA2
. This study presents an updated meta-analysis of the first genome-wide association screen performed in hallux valgus which did not identify genome-wide significant SNPs [10
]. This can, in part, be attributed to relatively modest sample sizes. We increased the sample by including data from the OAI and imputed genotypes to the most current HRC reference panel.
The lead variant, rs55807512, located in an intronic region of chromosome 1 within CLCA2
gene, had MAF around 4% and was not included in the first hallux valgus GWAS. Updating the imputation increased the number of low-frequency variants that were filtered out in previous analyses and can be studied reliably using the HRC reference panel. According to Entrez Gene database https://www.ncbi.nlm.nih.gov/gene
encodes a member of the calcium-activated chloride channel regulator (CLCR) family of proteins that regulates transport of chloride across the plasma membrane. Although another member of CLCA family, CLCA4
, has been reported to be associated with osteochondrosis in the horse [42
has not been associated with bone formation or any musculoskeletal disorders. However, COL24A1
may be the true gene of interest since our top hits were eQTLs for COL24A1
, a member of the collagen gene family, is developmentally expressed in cornea and bone by osteoblasts and regulates osteoblast differentiation and mineralization through interactions with integrins, which leads to the activation of the TGF-β/ Smad signaling pathway [43
]. Collagen type XXIV may be involved in structural differences between fibrillary collagens and affect fibril diameter [44
]. Abnormal collagen fibrils are associated with a wide spectrum of diseases of bone and cartilage, including hallux valgus [47
]. Uchiyama et al. [48
] demonstrated that feet with hallux valgus have different structures of collagen fibers compared to normal feet. This may be in response to continuous stress to the medial collateral ligament, one of the important joint stabilizers, and lead to altered organization of collagen I and collagen III fibrils that could leave the first metatarsophalangeal joint unprotected during gait [48
An important paralog of COL24A1
. Mutations in the COL5A1
gene, encoding the alpha 1 of type V collagen, have been identified in patients with Ehlers-Danlos syndrome [50
] which has been linked to hallux valgus [52
], Achilles tendinopathy [50
], acquired injuries such as ACL tears [53
], and with range of motion [50
None of the top SNPs identified from the previous hallux valgus meta-analysis became more significant in our updated meta-analysis. Of the four SNPs that met p < 5E-6 in men, only r10224956 and rs4476613, reached nominal significance (p = 0.02 and p = 0.001, respectively) in our study. Of the six SNPs that met p < 5E-6 in women, only rs12214759 and rs2242411 reached suggestive significance (p = 6.70E-06 and p = 6.67E-05, respectively) in our study with the same direction of effect. Furthermore, none of the previously identified SNPs were associated with hallux valgus in the UK Biobank GWAS.
One of the difficulties in studying the genetics of hallux valgus is the lack of a standardized phenotype. The method of measuring hallux valgus in studies collecting such data is not always clearly described. Furthermore, hallux valgus prevalence in studies using self-report data may be under-reported or inaccurate due to a lack of a validated assessment tool for this condition and lack of standardization for terms used in questionnaires (e.g., “bunion” and “hallux valgus”) [1
].An important advantage to our study is the detailed assessment of hallux valgus based on objective criteria rather than self-report. Although the presence of hallux valgus was not measured using weight-bearing radiographs of the feet, the reference standard of angle measurement, the clinical measures we used have been previously validated and were conducted by trained examiners which should minimize potential sources of error. These tools have been reported as alternatives to radiographs due to lower cost and lack of radiographic exposure, particularly for large-scale cohort studies that include asymptomatic participants [23
]. It is possible that in the absence of diagnostic tests and in-depth knowledge of participants’ medical history, several clinical diagnoses such as a bursa, prominent medial eminence of the first metatarsal, or bony swelling in joints with osteoarthritis can be misclassified as hallux valgus. However, these conditions are relatively rare in a general population and thus misclassification of these conditions likely had little effect on association results obtained from our meta-analysis. Importantly, another strength of our study is that it was not based on clinical cases only, but rather on a general population and therefore not affected by selection bias.
Our results should be interpreted in light of several limitations. First, hallux valgus was assessed across cohorts in two different ways (angular criteria vs. Manchester grading scale), which may lead to phenotypic misclassification and potential loss of statistical power. However, we assessed the distributions of the phenotype by cohort and compared distributions of key factors like age, sex, and BMI to ensure that there were no major differences. In all studies, participants categorized as ‘hallux valgus present’ were slightly older and were more likely to be female than those categorized as ‘no deformity’. As we noted previously, hallux valgus was less prevalent in FHS than in GOGO, JoCo, and OAI. This can be explained by the fact that FHS is a geographically-defined cohort study which did not specifically select individuals with or at risk of OA unlike OAI and GOGO. In addition, the lower prevalence of hallux valgus in FHS can be attributed to 1) differences in BMI and sex distributions and 2) environmental risk factors shared by family members leading to the development or prevention of hallux valgus [54
]. Despite efforts to minimize bias and ensure that hallux valgus was classified using a comparable method to JoCo, GOGO, and FHS as described by Menz and others, heterogeneity resulting from pooling data across studies may still be present and we can only speculate how results would change if the OAI cohort had been assessed for hallux valgus using angular criteria. We note though that it is unlikely that our primary findings were driven by OAI or any single study since I2
values were low and showed little evidence for study heterogeneity. Misclassification is a potential problem in the OAI where participants have less severe forms of the condition. Participants with mild deformity, however, were excluded from our main analyses, and including these participants in the sensitivity analysis did not affect our novel findings. Overall, any misclassification and heterogeneity would likely bias associations toward the null and would not affect our findings, but may limit power for additional discoveries. Second, we were unable to assess the severity of hallux valgus because we were limited by the measurements available in the participating studies. As noted previously, using ordinal measurements of hallux valgus such as the Manchester grade can improve the statistical power compared to a dichotomous trait such as hallux valgus presence or absence [10
]. Third, we were unable to replicate our findings in a different independent population with a comparable level of phenotyping. To the best of our knowledge, there are no other Caucasian cohorts with well-defined hallux valgus phenotypes and genome-wide genotyping. In the UK Biobank data that we used for replication, the lead variant was not associated with hallux valgus. This may be explained in part by the use of different phenotype criteria and different statistical models (logistic vs. linear regression, BMI adjustment). The prevalence of hallux valgus was much lower (~ 2%) in the UK Biobank compared to our meta-analysis (31–48%). Replication of our findings in additional studies with identical phenotype criteria and design will be important in the future. Fourth, we did not evaluate whether our findings are generalizable to individuals of other ancestry groups. We included only participants of European Ancestry in the analyses. Although GWAS data were available for 600 African American (AA) participants (268 from OAI and 332 from JoCoOA), we did not perform meta-analysis on AA samples due to a small sample size and limited statistical power.
In conclusion, we reported the largest hallux valgus meta-analysis on individuals of European ancestry. Hallux valgus is a common foot disorder that is greatly understudied, particularly its possible genetic aspects. Building upon prior work, we aimed to identify novel genetic variants associated with hallux valgus, and found a novel variant in the gene CLCA2. In addition, our top-hits in CLCA2 are eQTLs for a neighboring COL24A1 gene and potentially pinpoint the true gene of interest from an associated locus. While observed results were attenuated and signal diminished in sex-specific analyses, this study provides new insights into hallux valgus biology and the findings for additional replication and functional follow-up.
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