Genetic study identifies novel genes in developmental dysplasia of the hip

Soichiro Yoshino; Shibo Chen; Ryosuke Yamaguchi; Taishi Kurakazu; Konstantinos Hatzikotoulas; Yoshinao Koike; Daisuke Inoue; Yusuke Kohno; Kan Sasaki; Hyonmin Choe; Shoji Baba; Toshihiko Hara; Juji Ito; Yaichiro Okuzu; Kyohei Shiomoto; Tomoyuki Nakamura; Gaku Koyano; Tomohiro Shimizu; Koichi Kinoshita; Eiji Takahashi; Takeshi Utsunomiya; Daisuke Hara; Taishi Sato; Shinya Kawahara; Ayumi Kaneuji; Takuaki Yamamoto; Daisuke Takahashi; Tetsuya Jinno; Tsutomu Kawano; Koji Goto; Michiaki Takagi; Taro Mawatari; Yutaka Inaba; Tetsuro Nakamura; Tamon Kabata; Satoshi Hamai; Goro Motomura; Lorraine Southam; J. Mark Wilkinson; Eleftheria Zeggini; Shiro Ikegawa; Yasuharu Nakashima; Chikashi Terao

doi:10.1038/s41413-026-00514-8

Bone Research ›› 2026, Vol. 14 ›› Issue (1) :34 DOI: 10.1038/s41413-026-00514-8

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Genetic study identifies novel genes in developmental dysplasia of the hip

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¹Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

²Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

³Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany

⁴Munich Medical Research School (MMRS), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

⁵Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

⁶Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

⁷Department of Orthopaedic Surgery, Japan Community Healthcare Organization (JCHO) Kyushu Hospital, Kitakyushu, Japan

⁸Department of Orthopaedic Surgery, Yamagata Saisei Hospital, Yamagata, Japan

⁹Department of Orthopaedic Surgery, Yokohama City University, Yokohama, Japan

¹⁰Department of Orthopaedic Surgery, Hamanomachi Hospital, Fukuoka, Japan

¹¹Department of Orthopaedic Surgery, Aso Iizuka Hospital, Iizuka, Japan

¹²Department of Orthopaedic Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan

¹³Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

¹⁴Department of Orthopaedic Surgery, Kyushu Rosai Hospital, Kitakyushu, Japan

¹⁵Department of Othopaedic and Spine Surgery, Fukuoka Children’s Hospital, Fukuoka, Japan

¹⁶Department of Orthopaedic Surgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan

¹⁷Department of Orthopaedic Surgery, Fukuoka University Faculty of Medicine, Fukuoka, Japan

¹⁸Department of Orthopaedic Surgery, Kanazawa Medical University, Kahoku, Japan

¹⁹Department of Orthopaedic Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan

²⁰School of Medicine and Population Health, The University of Sheffield, Sheffield, UK

²¹Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Munich, Germany

²²Laboratory for Bone and Joint Diseases, RIKEN Center for Medical Sciences, Minato-ku, Tokyo, Japan

²³Clinical Research Center, Shizuoka General Hospital, Shizuoka-shi, Shizuoka, Japan

²⁴The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan

^a yamaguchi.ryosuke.183@m.kyushu-u.ac.jp

^b chikashi.terao@riken.jp

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Abstract

Developmental dysplasia of the hip (DDH), a morphological abnormality of the hip joint, is a well-recognized risk factor for hip osteoarthritis (OA). Much remains unknown about the genetic factors of DDH and its subtypes. To further understand its genetic basis, we conducted genome-wide association studies (GWASs) using a total of 1 085 Japanese DDH cases (including 788 hip dysplasia cases without dislocation and 297 cases with dislocated hip) and 24 000 controls. Additionally, we meta-analyzed with United Kingdom (UK) DDH GWAS and the largest hip OA GWAS to date. We identified three genome-wide significant novel loci, COL11A2, CALN1 and TRPM7, associated with hip dysplasia without dislocation. None of these signals were significant in dislocated hips, and additionally two of the signals had an opposite direction of association, suggesting distinct genetic architectures between the subtypes. The Japanese DDH GWAS identified five associated loci (VEGF-C, FOXC1, SMC2, SLC38A4, and TRPM7), and the trans-ancestry meta-analysis with UK revealed two loci (COL11A1 and GDF5) supported by strong trans-ancestry genetic correlation (r = 1.0). In total, nine loci were identified for DDH and its subtypes, with hip dysplasia without dislocation showing distinct genetic signals from hip dislocation. The meta-analysis of DDH and hip OA identified five novel signals for hip OA. Susceptibility loci and heritability enrichment analyses implicated pathways involving bone formation, collagen type XI trimer, and chondrocyte development, as well as their gene regulation, in DDH. These findings enhance understanding of the genetic architecture and biological pathways underlying DDH, providing new insights into its relationship with OA.

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Soichiro Yoshino, Shibo Chen, Ryosuke Yamaguchi, Taishi Kurakazu, Konstantinos Hatzikotoulas, Yoshinao Koike, Daisuke Inoue, Yusuke Kohno, Kan Sasaki, Hyonmin Choe, Shoji Baba, Toshihiko Hara, Juji Ito, Yaichiro Okuzu, Kyohei Shiomoto, Tomoyuki Nakamura, Gaku Koyano, Tomohiro Shimizu, Koichi Kinoshita, Eiji Takahashi, Takeshi Utsunomiya, Daisuke Hara, Taishi Sato, Shinya Kawahara, Ayumi Kaneuji, Takuaki Yamamoto, Daisuke Takahashi, Tetsuya Jinno, Tsutomu Kawano, Koji Goto, Michiaki Takagi, Taro Mawatari, Yutaka Inaba, Tetsuro Nakamura, Tamon Kabata, Satoshi Hamai, Goro Motomura, Lorraine Southam, J. Mark Wilkinson, Eleftheria Zeggini, Shiro Ikegawa, Yasuharu Nakashima, Chikashi Terao. Genetic study identifies novel genes in developmental dysplasia of the hip. Bone Research, 2026, 14(1): 34 DOI:10.1038/s41413-026-00514-8

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