Evidence map›Paper›PMID 42396272›Full record

ArticlemedRxiv : the preprint server for health sciences2026

Dissecting the genetic architecture of knee alignment reveals its contribution to osteoarthritis risk.

Mijin Jung, Faten Alomar, Clarissa R Coveney, Shibo Chen, Sarah E Orr, Jolet Mimpen, Marina Nikolic, Kaitlyn A Flynn, Yuandan Zhang, Raja Ebsim and 16 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

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5 · Who and what money

Authors and funding

26 authors.

Mijin JungMusculoskeletal Research Unit, University of Bristol, Bristol, UK.
Faten AlomarDivision of Informatics, Imaging and Data Sciences, The University of Manchester, Manchester, UK.
Clarissa R CoveneyDepartment of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
Shibo ChenInstitute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Sarah E OrrBiosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK.
Jolet MimpenNuffield Department of Orthopaedics Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
Marina NikolicNuffield Department of Orthopaedics Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
Kaitlyn A FlynnMater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
Yuandan ZhangMater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
Raja EbsimDivision of Informatics, Imaging and Data Sciences, The University of Manchester, Manchester, UK.
Fiona R SaundersAberdeen Centre for Research Excellence in Musculoskeletal Health, University of Aberdeen, Aberdeen, UK.
Jennifer S GregoryAberdeen Centre for Research Excellence in Musculoskeletal Health, University of Aberdeen, Aberdeen, UK.
Richard M AspdenAberdeen Centre for Research Excellence in Musculoskeletal Health, University of Aberdeen, Aberdeen, UK.
Nicholas C HarveyMedical Research Council Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK.
Claudia LindnerDivision of Informatics, Imaging and Data Sciences, The University of Manchester, Manchester, UK.
Simon Gf AbramMusculoskeletal Research Unit, University of Bristol, Bristol, UK.
Chrissy HammondSchool of Biochemistry and Biomedical Sciences, University of Bristol, Bristol, UK.
George Davey SmithMedical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Eleftheria ZegginiInstitute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Sarah SnellingNuffield Department of Orthopaedics Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
Terence D CapelliniDepartment of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
Sarah J RiceBiosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK.
John P KempMater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
Jonathan H TobiasMusculoskeletal Research Unit, University of Bristol, Bristol, UK.
Tim CootesDivision of Informatics, Imaging and Data Sciences, The University of Manchester, Manchester, UK.
Benjamin G FaberMusculoskeletal Research Unit, University of Bristol, Bristol, UK.

Funding

Molecular architecture of the human knee joint and pelvis at single cell resolutionR01AR081274 · NIAMS · HARVARD UNIVERSITY · PI Terence D Capellini, April Marie Craft · 2023 to 2026
$3.1M
NIAMS NIH HHS R01 AR081274Wellcome Trust
6 · The paper itself

Abstract

Objectives: To investigate the biological and clinical relevance of knee alignment in osteoarthritis by integrating population-scale imaging, genome-wide association, and functional genetic analyses. Methods: Femorotibial angle was derived from dual-energy X-ray absorptiometry scans in UK Biobank using machine-learning methods. Associations with knee and hip osteoarthritis outcomes were assessed. A genome-wide association study of mean femorotibial angle was performed, followed by fine-mapping and pathway enrichment analyses. Mendelian randomization was used to explore potential causal relationships. Results: Varus alignment was strongly and progressively associated with knee pain, knee osteoarthritis, and total knee replacement (HR 3.42 [95% CI 2.92, 4.02]), with no association observed for hip osteoarthritis. GWAS identified 20 independent loci associated with femorotibial angle, enriched for pathways related to skeletal development, cartilage biology, and endochondral ossification. Post-GWAS analyses demonstrated regulatory effects across fetal and adult joint tissues, supporting life course influences on alignment. Genetic correlation analyses showed shared architecture between femorotibial angle and knee osteoarthritis. Causal analyses suggested that genetic liability to osteoarthritis reduces femorotibial angle (β -0.11 [-0.16, -0.06]), while evidence for an overall causal effect of femorotibial angle on osteoarthritis risk was limited (OR 0.93 [0.79, 1.10]). Conclusions: Knee alignment and susceptibility to knee osteoarthritis are partially genetically determined. At the population level, these genetic determinants support a causal effect of osteoarthritis on knee alignment, whereas evidence for a causal effect of alignment on knee osteoarthritis was limited. Furthermore, this study identifies novel genetic loci linking knee alignment with pathways involved in skeletal development and cartilage biology relevant to osteoarthritis.

Indexed as

EpidemiologyGeneticsKnee alignmentMachine-learningOsteoarthritisValgusVarus

Identifiers

PMID42396272
PMCPMC13321165

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LicenceCC BY
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.