Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans

Abstract

Objective Hallux valgus (HV) affects ~36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV. Methods HV was assessed in 3 Caucasian cohorts (n=2,263, n=915, and n=1,231 participants, respectively). In each cohort, a GWAS was conducted using 2.5M imputed single nucleotide polymorphisms (SNPs). Mixed-effect regression with the additive genetic model adjusted for age, sex, weight and within-family correlations was used for both sex-specific and combined analyses. To combine GWAS results across cohorts, fixed-effect inverse-variance meta-analyses were used. Following meta-analyses, top-associated findings were also examined in an African American cohort (n=327). Results The proportion of HV variance explained by genome-wide genotyped SNPs was 50% in men and 48% in women. A higher proportion of genetic determinants of HV was sex-specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=5.46×10−7); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=7.21×10−7). Genome-wide significant SNP-by-sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p-value =4.1×10−9). The association signals diminished when combining men and women. Conclusion Findings suggest that the potential pathophysiological mechanisms of HV are complex and strongly underlined by sex-specific interactions. The identified genetic variants imply contribution of biological pathways observed in osteoarthritis as well as new pathways, influencing skeletal development and inflammation.

Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank

“…The phecode encompassed cervical erosion and ectropion, stricture and stenosis, cervical incompetence, and requirement of pregnancy-related care for cervical abnormalities, suggesting this finding may be related to risk of recurrent pregnancy loss, that has previously been associated with the ε2 and ε4 alleles [26] . The ε2ε2 genotype was also associated with hallux valgus , suggesting the APOE ε2 allele may represent another risk allele for this highly heritable foot disorder that has been linked to susceptibility loci near genes encoding Axin 2 ( AXIN2 ), Esterase D ( ESD ) [27] , vitamin D receptor ( VDR ) [28] , and tumour necrosis factor ( TNF ) [29] . It should be noted that while significant associations were found with ε2ε2, the case numbers for some outcomes were limited, and further targeted studies with greater population sizes are warranted.…”

Epidemiology of Shoe Wearing Patterns Over Time in Older Women: Associations With Foot Pain and Hallux Valgus

“…Although the cause of hallux valgus is considered to be multifactorial (involving biomechanical (30) and genetic (31,32) factors), constrictive footwear may contribute to its development by holding the hallux in an abducted position, leading to soft tissue and osseous remodeling over time (29). We found a graded increase in the risk of hallux valgus with increasing narrowness of the toe box in footwear worn between 20 and 29 years of age, and to a lesser extent, at ages 30 and 39 years.…”

Early initiation of zoledronic acid does not impact bone healing or clinical outcomes of hallux valgus orthomorphia

“… 4 HV is the most common foot disorder in adults and is more prevalent among older than younger individuals and among women than men, and it profoundly affects women’s quality of life. 2 , 3 With the development of foot and ankle surgery, increasingly more patients with severe HV are presenting to hospitals for surgical treatment. Among patients who undergo surgical orthomorphia for HV, postmenopausal women account for a high proportion because of the long-term use of high-heeled shoes in many of these women; such shoes increase the pressure under the metatarsal heads, limit motion of the first MTJ, and increase the stiffness of the Achilles tendon.…”

“… 1 Hallux valgus (HV) is a highly prevalent forefoot deformity that is more prevalent among older than younger individuals and among women than men. 2 HV is also associated with quality of life and general health. 3 , 4 Symptomatic HV, which is usually due to osteoarthritis in the first metatarsophalangeal joint (MTJ) or the first tarsometatarsal joint (FTJ), must be treated by surgery.…”