Yi-Hsiang Hsu1, Youfang Liu2, Marian T Hannan3, William Maixner4, Shad B Smith4, Luda Diatchenko5, Yvonne M Golightly6, Hylton B Menz7, Virginia B Kraus8, Michael Doherty9, A G Wilson10, Joanne M Jordan11. 1. Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, Massachusetts, USA Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2. Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, USA. 3. Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 4. Center for Pain Research and Innovation, University of North Carolina School of Dentistry, Chapel Hill, North Carolina, USA. 5. Center for Pain Research and Innovation, University of North Carolina School of Dentistry, Chapel Hill, North Carolina, USA Alan Edwards Center for Research on Pain, McGill University, Montreal, Quebec, Canada. 6. Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, USA Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA Injury Prevention Research Center, University of North Carolina, Chapel Hill, North Carolina, USA. 7. Lower Extremity and Gait Studies Program, La Trobe University, Bundoora, Australia. 8. Department of Medicine, The Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA. 9. Department of Academic Rheumatology, University of Nottingham, Nottingham, UK. 10. Department of Infection and Immunity, The University of Sheffield Medical School, UK. 11. Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, USA Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA Department of Orthopedics, University of North Carolina, Chapel Hill, North Carolina, USA.
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 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
GWAS; candidate genes; genetic variants; hallux valgus
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