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

Abstract

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.

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Item Type:	Article
Authors/Creators:	Hatzikotoulas, K. https://orcid.org/0000-0002-4699-3672 Roposch, A. Case Control Consortium, D.D.H. Shah, K.M. Clark, M.J. Bratherton, S. Limbani, V. Steinberg, J. Zengini, E. Warsame, K. Ratnayake, M. Tselepi, M. Schwartzentruber, J. Loughlin, J. Eastwood, D.M. Zeggini, E. Wilkinson, J.M. https://orcid.org/0000-0001-5577-3674
Copyright, Publisher and Additional Information:	© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 31 May 2018 Published (online): 31 May 2018 Accepted: 13 April 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	10 Aug 2018 11:07
Last Modified:	10 Aug 2018 11:07
Published Version:	https://doi.org/10.1038/s42003-018-0052-4
Status:	Published
Publisher:	Nature Publishing Group
Refereed:	Yes
Identification Number:	10.1038/s42003-018-0052-4
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:133686

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

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