Aging of the Spine: Characterizing genetic and physiological determinants of spinal curvature

Aging of the Spine: Characterizing genetic and physiological determinants of spinal curvature | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Aging of the Spine: Characterizing genetic and physiological determinants of spinal curvature Eugene Melamud, Frances Wang, J. Ruby, Anurag Sethi, Matthew Veras, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3992616/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Jul, 2025 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Abstract Increased spinal curvature is one of the most recognizable aging traits in the human population. However, despite high prevalence, the etiology of this condition remains poorly understood. To gain better insight into the physiological, biochemical, and genetic risk factors involved, we developed a novel machine learning method to automatically derive thoracic kyphosis and lumbar lordosis angles from dual-energy X-ray absorptiometry (DXA) scans in the UK Biobank Imaging cohort. In 41,212 participants, we find that on average males and females gain 2.42° kyphotic and 1.48° lordotic angle per decade of life. Increased spinal curvature was strongly associated with decreased muscle mass and bone mineral density. Adiposity had opposing associations, with decreased kyphosis and increased lordosis. To gain further insight into the molecular mechanisms involved, we carried out a genome-wide association study and identified several risk loci associated with both traits. Using Mendelian randomization, we further show that genes fundamental to the maintenance of musculoskeletal functon(COL11A1, PTHLH, ETFA, TWIST1) and cellular homeostasis such as RNA transcription and DNA repair (RAD9A, MMS22L, HIF1A, RAB28) are likely involved in increased spinal curvature. Health sciences/Medical research/Biomarkers/Predictive markers Health sciences/Diseases/Metabolic disorders Health sciences/Biomarkers/Prognostic markers Kyphosis Lordosis Spine Curvature Skeletomuscular Aging Cobb Angles Machine Learning GWAS Full Text Additional Declarations Yes there is potential Competing Interest. This research was supported by Calico Life Sciences LLC and conducted under the UK Biobank. Supplementary Files SupplementalMethodsKyphosisLordosis.docx SupplementaryFiguresKyphosisLordosis.pdf Cite Share Download PDF Status: Published Journal Publication published 12 Jul, 2025 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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