Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans.
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.
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.
Yi-Hsiang
YH
Hsu
Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Youfang
Y
Liu
Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Marian T
MT
Hannan
Center for Pain Research and Innovation, University of North Carolina School of Dentistry, Chapel Hill, North Carolina, USA.
William
W
Maixner
Center for Pain Research and Innovation, University of North Carolina School of Dentistry, Chapel Hill, North Carolina, USA.
Shad B
SB
Smith
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.
Luda
L
Diatchenko
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.
Yvonne M
YM
Golightly
Lower Extremity and Gait Studies Program, La Trobe University, Bundoora, Australia.
Hylton B
HB
Menz
Department of Medicine, The Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Virginia B
VB
Kraus
Department of Academic Rheumatology, University of Nottingham, Nottingham, UK.
Michael
M
Doherty
Department of Infection and Immunity, The University of Sheffield Medical School, UK.
A G
AG
Wilson
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.
Joanne M
JM
Jordan
D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D060466:Axin Protein / Q000235:genetics; D043182:Carboxylesterase / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006215:Hallux Valgus / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012737:Sex Factors; D044465:White People / Q000235:genetics*
C491761:AXIN2 protein, human; D060466:Axin Protein; C501064:MRGPRX3 protein, human; D043562:Receptors, G-Protein-Coupled; D043182:Carboxylesterase; C020118:ESD protein, human
GWAS; candidate genes; genetic variants; hallux valgus