Genome-wide meta-analysis identified novel variant associated with hallux valgus in Caucasians

Abstract

Background: Hallux valgus, one of the most common structural foot deformities, is highly heritable. However, previous efforts to elucidate the genetic underpinnings of hallux valgus through a genome-wide association study (GWAS) conducted in 4409 Caucasians did not identify genome-wide significant associations with hallux valgus in both gender-specific and sex-combined GWAS meta-analyses. In this analysis, we add newly available data and more densely imputed genotypes to identify novel genetic variants associated with hallux valgus.

Methods: A total of 5925 individuals of European Ancestry were categorized into two groups: 'hallux valgus present' (n = 2314) or 'no deformity' (n = 3611) as determined by trained examiners or using the Manchester grading scale. Genotyping was performed using commercially available arrays followed by imputation to the Haplotype Reference Consortium (HRC) reference panel version 1.1. We conducted both sex-specific and sex-combined association analyses using logistic regression and generalized estimating equations as appropriate in each cohort. Results were then combined in a fixed-effects inverse-variance meta-analyses. Functional Mapping and Annotation web-based platform (FUMA) was used for positional mapping, gene and gene-set analyses.

Results: We identified a novel locus in the intronic region of CLCA2 on chromosome 1, rs55807512 (OR = 0.48, p = 2.96E-09), an expression quantitative trait locus for COL24A1, a member of the collagen gene family.

Conclusion: In this report of the largest GWAS of hallux valgus to date, we identified a novel genome-wide significant locus for hallux valgus. Additional replication and functional follow-up will be needed to determine the functional role of this locus in hallux valgus biology.

Keywords: Genetic epidemiology; Genome-wide; Muscle disease; Rheumatology.

Fig. 1

Manhattan plot represents the p-values of the entire GWAS on genomic scale. The p-values are ordered by chromosome and position on the corresponding chromosome (x-axis). The value on the y-axis is the (–log10) of the p-value and is equivalent to the number of zeros after the decimal point plus one. The graph looks like a Manhattan skyline because of local correlation of SNPs. The red line shows the threshold for genome-wide significance

Fig. 2

Forest plot of rs55807512 (CLCA2, chr1) association with hallux valgus in the meta-analysis

Fig. 3

Regional association plot of CLCA2 locus

Fig. 4

Circos plots of mapped gene on chromosome 1 locus. Genomic risk loci are highlighted in blue. Genes are mapped by 3-D chromatin interaction (orange) or eQTLs (green), or both (red)