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Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans
  1. Yi-Hsiang Hsu1,2,3,4,
  2. Youfang Liu5,
  3. Marian T Hannan1,4,
  4. William Maixner6,
  5. Shad B Smith6,
  6. Luda Diatchenko6,7,
  7. Yvonne M Golightly5,8,9,
  8. Hylton B Menz10,
  9. Virginia B Kraus11,
  10. Michael Doherty12,
  11. AG Wilson13,
  12. Joanne M Jordan5,8,14,15
  1. 1Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA
  2. 2Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  3. 3Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, Massachusetts, USA
  4. 4Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
  5. 5Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, USA
  6. 6Center for Pain Research and Innovation, University of North Carolina School of Dentistry, Chapel Hill, North Carolina, USA
  7. 7Alan Edwards Center for Research on Pain, McGill University, Montreal, Quebec, Canada
  8. 8Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  9. 9Injury Prevention Research Center, University of North Carolina, Chapel Hill, North Carolina, USA
  10. 10Lower Extremity and Gait Studies Program, La Trobe University, Bundoora, Australia
  11. 11Department of Medicine, The Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA
  12. 12Department of Academic Rheumatology, University of Nottingham, Nottingham, UK
  13. 13Department of Infection and Immunity, The University of Sheffield Medical School, UK
  14. 14Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
  15. 15Department of Orthopedics, University of North Carolina, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr Marian T Hannan, Hebrew SeniorLife Institute for Aging Research, 1200 Centre Street, Boston, MA 02131-1097, USA; hannan{at}


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 three Caucasian cohorts (n=2263, n=915 and n=1231 participants, respectively). In each cohort, a GWAS was conducted using 2.5 M imputed 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 were sex specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=0.000000546×10−7); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=0.000000721×10−7). Genome-wide significant SNP-by-sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p value =0.0000000041×10−9). The association signals diminished when combining men and women.

Conclusions The 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.

  • hallux valgus
  • GWAS
  • genetic variants
  • candidate genes

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