TY - JOUR
T1 - Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5
AU - The DDH Case Control Consortium
AU - Hatzikotoulas, Konstantinos
AU - Roposch, Andreas
AU - Wainwright, Andrew
AU - Theologis, Tim
AU - Clarke, Nicholas M.P.
AU - Dwyer, Jonathan S.M.
AU - Hashemi-Nejad, Aresh
AU - Kiely, Nigel
AU - Katchburian, Marcos
AU - Nicolaou, Nicolas
AU - Page, Johnathan
AU - Gargan, Martin
AU - Bruce, Colin
AU - Sanghrajka, Anish
AU - Marshall, Paul
AU - Flowers, Mark
AU - Malaga-Shaw, Olivia
AU - Mitchell, Piers
AU - Ben Holroyd, Holroyd
AU - Ramachandran, Manoj
AU - Shah, Karan M.
AU - Clark, Matthew J.
AU - Bratherton, Selina
AU - Limbani, Vasanti
AU - Steinberg, Julia
AU - Zengini, Eleni
AU - Warsame, Kaltuun
AU - Ratnayake, Madhushika
AU - Tselepi, Maria
AU - Schwartzentruber, Jeremy
AU - Loughlin, John
AU - Eastwood, Deborah M.
AU - Zeggini, Eleftheria
AU - Wilkinson, J. Mark
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Developmental dysplasia of the hip (DDH) is the most common skeletal developmental disease. However, its genetic architecture is poorly understood. We conduct the largest DDH genome-wide association study to date and replicate our findings in independent cohorts. We find the heritable component of DDH attributable to common genetic variants to be 55% and distributed equally across the autosomal and X-chromosomes. We identify replicating evidence for association between GDF5 promoter variation and DDH (rs143384, effect allele A, odds ratio 1.44, 95% confidence interval 1.34–1.56, P = 3.55 × 10−22). Gene-based analysis implicates GDF5 (P = 9.24 × 10−12), UQCC1 (P = 1.86 × 10− 10), MMP24 (P = 3.18 × 10−9), RETSAT (P = 3.70 × 10− 8) and PDRG1 (P = 1.06 × 10− 7) in DDH susceptibility. We find shared genetic architecture between DDH and hip osteoarthritis, but no predictive power of osteoarthritis polygenic risk score on DDH status, underscoring the complex nature of the two traits. We report a scalable, time-efficient recruitment strategy and establish for the first time to our knowledge a robust DDH genetic association locus at GDF5.
AB - Developmental dysplasia of the hip (DDH) is the most common skeletal developmental disease. However, its genetic architecture is poorly understood. We conduct the largest DDH genome-wide association study to date and replicate our findings in independent cohorts. We find the heritable component of DDH attributable to common genetic variants to be 55% and distributed equally across the autosomal and X-chromosomes. We identify replicating evidence for association between GDF5 promoter variation and DDH (rs143384, effect allele A, odds ratio 1.44, 95% confidence interval 1.34–1.56, P = 3.55 × 10−22). Gene-based analysis implicates GDF5 (P = 9.24 × 10−12), UQCC1 (P = 1.86 × 10− 10), MMP24 (P = 3.18 × 10−9), RETSAT (P = 3.70 × 10− 8) and PDRG1 (P = 1.06 × 10− 7) in DDH susceptibility. We find shared genetic architecture between DDH and hip osteoarthritis, but no predictive power of osteoarthritis polygenic risk score on DDH status, underscoring the complex nature of the two traits. We report a scalable, time-efficient recruitment strategy and establish for the first time to our knowledge a robust DDH genetic association locus at GDF5.
UR - https://www.scopus.com/pages/publications/85059161112
U2 - 10.1038/s42003-018-0052-4
DO - 10.1038/s42003-018-0052-4
M3 - Article
C2 - 30273415
AN - SCOPUS:85059161112
SN - 2399-3642
VL - 1
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 56
ER -