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

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 degree 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 function (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. ### Competing Interest Statement This research was supported by Calico Life Sciences LLC and conducted under UK Biobank Resource application number 18448. ### Clinical Protocols ### Funding Statement This research was funded by Calico Life Sciences LLC. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All UKBB data used in this study were anonymized and were accessed through project number 18448. The National Research Ethics Service Committee of North West-Haydock (REC reference: 11/NW/0382) gave ethical approval to the UKBB project for this work. Signed informed consent was obtained electronically from all participants (https://biobank.ctsu.ox.ac.uk/crystal/crystal/docs/Consent.pdf). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data from the UK Biobank is available on request (https://www.ukbiobank.ac.uk/).