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Contribution of rare variation to degenerative orthopedic diseases

Anker-Hansen, Christian LU orcid ; Manderstedt, Eric LU ; Lind-Halldén, Christina LU ; Halldén, Christer LU and Zöller, Bengt LU orcid (2026) In Osteoarthritis and Cartilage Open 8(2).
Abstract

Objective: Degenerative orthopedic diseases (DODs) such as osteoporosis, osteoarthritis, spondylosis, spinal stenosis, and disc herniation are common disorders. Both common and rare genetic risk factors may contribute to DODs, but few large-scale whole-exome sequencing studies elucidating the contribution of rare variations to DODs have been published. The updated version of the Astra Zeneca portal (https://azphewas.com) was used to access gene collapsing analysis of rare variations for DODs. Method: One published UK Biobank portal: the updated Astra Zeneca portal based on whole genome sequencing (N = 484,111), was used to access gene collapsing analysis of rare qualifying variants (QVs) for fourteen DODs. A conservative threshold (p ≤... (More)

Objective: Degenerative orthopedic diseases (DODs) such as osteoporosis, osteoarthritis, spondylosis, spinal stenosis, and disc herniation are common disorders. Both common and rare genetic risk factors may contribute to DODs, but few large-scale whole-exome sequencing studies elucidating the contribution of rare variations to DODs have been published. The updated version of the Astra Zeneca portal (https://azphewas.com) was used to access gene collapsing analysis of rare variations for DODs. Method: One published UK Biobank portal: the updated Astra Zeneca portal based on whole genome sequencing (N = 484,111), was used to access gene collapsing analysis of rare qualifying variants (QVs) for fourteen DODs. A conservative threshold (p ≤ 5 × 10−8) was used to decrease the risk of spurious associations. Odds ratios (ORs) with 95 % confidence intervals (CIs) were estimated. Results: One previously osteoporosis-linked gene (LRP5) was identified (p-value = 3.0 × 10−13, OR = 1.55 (95%CI 1.38–1.73)). Two other significant genes were identified: the TET2 gene that was linked to dorsalgia (p-value = 8.3 × 10−9, OR = 1.54 (95%CI 1.33–1.77)) and the SMAD6 gene that was associated with spinal stenosis (p-value = 1.7 × 10−9, OR = 2.70 (95%CI 2.02–3.61)) and other spondylopathies (p-value = 9.0 × 10−11, OR = 2.41 (95%CI 1.89–3.07)). Among controls 1.10 % were carriers of LRP5 QVs, 0.29 % of controls carried TET2 QVs, and 0.20 %–0.21 % of controls carried SMAD6 QVs. Conclusion: One established osteoporosis gene (LRP5) and two other DODs genes (TET2 and SMAD6) were identified using gene collapsing analyses. Only a small number of genes reached the chosen significance threshold under the current phenotype definitions and analytic framework.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Exome sequencing, Genetics, Molecular epidemiology, Musculoskeletal diseases, Osteoarthritis, Osteoporosis
in
Osteoarthritis and Cartilage Open
volume
8
issue
2
article number
100767
publisher
Elsevier
external identifiers
  • scopus:105032150706
  • pmid:41859529
ISSN
2665-9131
DOI
10.1016/j.ocarto.2026.100767
language
English
LU publication?
yes
id
fca74e28-26d3-4a1a-934f-3cbdbeea2f29
date added to LUP
2026-04-23 15:36:28
date last changed
2026-06-04 18:23:48
@article{fca74e28-26d3-4a1a-934f-3cbdbeea2f29,
  abstract     = {{<p>Objective: Degenerative orthopedic diseases (DODs) such as osteoporosis, osteoarthritis, spondylosis, spinal stenosis, and disc herniation are common disorders. Both common and rare genetic risk factors may contribute to DODs, but few large-scale whole-exome sequencing studies elucidating the contribution of rare variations to DODs have been published. The updated version of the Astra Zeneca portal (https://azphewas.com) was used to access gene collapsing analysis of rare variations for DODs. Method: One published UK Biobank portal: the updated Astra Zeneca portal based on whole genome sequencing (N = 484,111), was used to access gene collapsing analysis of rare qualifying variants (QVs) for fourteen DODs. A conservative threshold (p ≤ 5 × 10<sup>−8</sup>) was used to decrease the risk of spurious associations. Odds ratios (ORs) with 95 % confidence intervals (CIs) were estimated. Results: One previously osteoporosis-linked gene (LRP5) was identified (p-value = 3.0 × 10<sup>−13</sup>, OR = 1.55 (95%CI 1.38–1.73)). Two other significant genes were identified: the TET2 gene that was linked to dorsalgia (p-value = 8.3 × 10<sup>−9</sup>, OR = 1.54 (95%CI 1.33–1.77)) and the SMAD6 gene that was associated with spinal stenosis (p-value = 1.7 × 10<sup>−9</sup>, OR = 2.70 (95%CI 2.02–3.61)) and other spondylopathies (p-value = 9.0 × 10<sup>−11</sup>, OR = 2.41 (95%CI 1.89–3.07)). Among controls 1.10 % were carriers of LRP5 QVs, 0.29 % of controls carried TET2 QVs, and 0.20 %–0.21 % of controls carried SMAD6 QVs. Conclusion: One established osteoporosis gene (LRP5) and two other DODs genes (TET2 and SMAD6) were identified using gene collapsing analyses. Only a small number of genes reached the chosen significance threshold under the current phenotype definitions and analytic framework.</p>}},
  author       = {{Anker-Hansen, Christian and Manderstedt, Eric and Lind-Halldén, Christina and Halldén, Christer and Zöller, Bengt}},
  issn         = {{2665-9131}},
  keywords     = {{Exome sequencing; Genetics; Molecular epidemiology; Musculoskeletal diseases; Osteoarthritis; Osteoporosis}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Elsevier}},
  series       = {{Osteoarthritis and Cartilage Open}},
  title        = {{Contribution of rare variation to degenerative orthopedic diseases}},
  url          = {{http://dx.doi.org/10.1016/j.ocarto.2026.100767}},
  doi          = {{10.1016/j.ocarto.2026.100767}},
  volume       = {{8}},
  year         = {{2026}},
}