Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5

• Published in: Communications biology Vol. 1; no. 1; p. 56
• Main Authors: Hatzikotoulas, Konstantinos, Roposch, Andreas, Shah, Karan M., Clark, Matthew J., Bratherton, Selina, Limbani, Vasanti, Steinberg, Julia, Zengini, Eleni, Warsame, Kaltuun, Ratnayake, Madhushika, Tselepi, Maria, Schwartzentruber, Jeremy, Loughlin, John, Eastwood, Deborah M., Zeggini, Eleftheria, Wilkinson, J. Mark
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2018; Nature Publishing Group
• Subjects: 45; 45/22; 45/43; 631/208/205/2138; 631/208/457; 692/699/1670/1669; 692/699/1670/407; Arthritis; Biology; Biomedical and Life Sciences; Developmental disabilities; Dysplasia; Genetic diversity; Genome-wide association studies; Genomes; Growth differentiation factor 5; Hip; Life Sciences; Osteoarthritis; Polygenic inheritance
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-018-0052-4

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
.
Konstantinos Hatzikotoulas et al. report the largest genome-wide association study to date for developmental dysplasia of the hip using national clinical audit data from the UK. They find a significant association with the
GDF5
locus and evidence for shared genetic architecture with hip osteoarthritis.