COL11A1 is associated with developmental dysplasia of the hip and secondary osteoarthritis in the HUNT study

Kaya Kvarme Jacobsen; Sigrid Børte; Lene Bjerke Laborie; Hege Kristiansen; Annette Schäfer; HUNT All-In Pain; Trude Gundersen; Tetyana Zayats; Bendik Kristoffer Slagsvold Winsvold; Karen Rosendahl

doi:10.1016/j.ocarto.2023.100424

COL11A1 is associated with developmental dysplasia of the hip and secondary osteoarthritis in the HUNT study

Osteoarthr Cartil Open. 2023 Dec 16;6(1):100424. doi: 10.1016/j.ocarto.2023.100424. eCollection 2024 Mar.

Authors

Kaya Kvarme Jacobsen¹, Sigrid Børte^{2

3

4}, Lene Bjerke Laborie^{5

6}, Hege Kristiansen^{7

8}, Annette Schäfer⁷; HUNT All-In Pain; Trude Gundersen^{5

29}, Tetyana Zayats^{28

30

31}, Bendik Kristoffer Slagsvold Winsvold^{4

9

19}, Karen Rosendahl^{32

33}

Collaborators

HUNT All-In Pain:
Amy E Martinsen^{9

3

10}, Anne Heidi Skogholt¹¹, Ben M Brumpton¹¹, Cristen J Willer¹², Egil A Fors¹³, Espen S Kristoffersen^{9

14

15}, Ingrid Heuch⁹, Ingunn Mundal¹⁶, John-Anker Zwart^{9

3

10}, Jonas B Nielsen^{10

11}, Kjersti Storheim^{17

18}, Knut Hagen¹⁹, Kristian Bernhard Nilsen^{18

19}, Kristian Hveem^{10

20

21}, Lars G Fritsche²², Laurent F Thomas^{10

23

24

25}, Linda M Pedersen⁹, Maiken E Gabrielsen¹⁰, Marie U Lie^{3

17}, Synne Ø Stensland^{17

26}, Wei Zhou^{27

28}

Affiliations

¹ Department of Orthopedic Surgery, District General Hospital of Førde, Førde, Norway.
² Research and Communication Unit for Musculoskeletal Health, Division of Clinical Neuroscience, Oslo University Hospital, Ullevaal, Oslo, Norway.
³ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁴ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
⁵ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁶ Section for Pediatric Radiology, Department of Radiology, Haukeland University Hospital, Bergen, Norway.
⁷ Department of Paediatrics, District General Hospital of Førde, Førde, Norway.
⁸ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁹ Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
¹⁰ K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
¹¹ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
¹² Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
¹³ Department of General Practice, University of Oslo, Oslo, Norway.
¹⁴ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
¹⁵ Department of Health Science, Molde University College, Molde, Norway.
¹⁶ Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
¹⁷ Department of physiotherapy, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway.
¹⁸ Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
¹⁹ Department of Neurology, Oslo University Hospital, Oslo, Norway.
²⁰ HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
²¹ Department of Research, Innovation and Education, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²² Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
²³ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
²⁴ BioCore - Bioinformatics Core Facility, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
²⁵ Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁶ Norwegian Centre for Violence and Traumatic Stress Studies, Oslo, Norway.
²⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
²⁹ Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway.
³⁰ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³¹ PROMENTA, Department of Psychology, University of Oslo, Oslo, Norway.
³² Department of Radiology, University Hospital of North-Norway, Tromsø, Norway.
³³ Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromsø, Norway.

Abstract

Objective: Developmental dysplasia of the hip (DDH) is a congenital condition affecting 2-3% of all infants. DDH increases the risk of osteoarthritis, is the cause of 30 % of all total hip arthroplasties (THAs) in adults <40 years of age and can result in loss of life quality. Our aim was to explore the genetic background of DDH in order to improve diagnosis, management and longterm outcome.

Design: We used the large, ongoing, longitudinal Trøndelag Health Study (HUNT) database. Case definition was based on ICD-9/-10 diagnoses of DDH, or osteoarthritis secondary to DDH. Analyses were performed using SAIGE software, with covariates including sex, batch, birth year and principal components. We included only single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) $\geq$ 0.01, R² $\geq$ 0.8 and Hardy-Weinberg equilibrium (HWE) P-value $\geq$ 0.0001. Significance level was set at p < 5 × 10^-8. Meta-analysis using data from DDH and primary osteoarthritis genome-wide association studies (GWASs) was done using METAL software. The study was approved by the regional ethical committee.

Results: Analysis included 69,500 individuals, of which 408 cases, and 8,531,386 SNPs. Two SNPs near COL11A1 were significantly associated with DDH; rs713162 ( $β$ = -0.43, SE = 0.07, p = 8.4 × 10^-9) and rs6577334 ( $β$ = -0.43, SE = 0.08, p = 8.9 × 10^-9). COL11A1 has previously been associated with acetabular dysplasia and osteoarthritis. Meta-analysis supported previous GWAS findings of both DDH and primary osteoarthritis.

Conclusions: This large, genome-wide case-control study indicates an association between COL11A1 and DDH and is an important contribution to investigating the etiology of DDH, with further research needed.

Keywords: COL11A1; Developmental dysplasia of the hip; Genetic; HUNT; Hip dysplasia.