The genetic architecture of MRI derived human cervical spinal cord morphology reveals sensory-motor axis and biomarkers of neurological and systemic diseases

ABSTRACT The spinal cord is critical to motor, sensory, autonomic function, and increasingly implicated in neurological disease and human health, yet its genetic architecture remains largely unexplored. We performed the first large-scale phenotyping of the upper cervical spinal cord (C1-C3) structure using brain magnetic resonance imaging from over 40,000 UK Biobank participants, extracting shape metrics including cross-sectional area, diameters, and eccentricity. We identified a total of 179 independent genome-wide significant variants, with cervical spinal cord morphology showing moderate to high SNP-based heritability (0.16 to 0.42). We also uncovered sex-specific genetic signals, highlighting potential biological sex differences in spinal cord development. In addition, spinal cord structure was associated with a wide range of neurological, metabolic, and systemic conditions, such as multiple sclerosis, neuropathies, diabetes, and attention-deficit/hyperactivity disorder. These findings establish the cervical spinal cord as a genetically informative and health relevant structure, offering new opportunities to study its role in disease mechanisms and human health. Competing Interest Statement The authors have declared no competing interest. Funding Statement ZFG is supported by an Australian National Health and Medical Research Council (NHMRC) EL1 Investigator Grant (2034743). MB was supported by an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (GNT1195236). 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 genetics, health related information, and imaging data described in this paper are publicly available to registered researchers through the UKB data-access protocol. Additional information about registration for access to the data are available at: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 Availability All genetics, health related information, and imaging data described in this paper are publicly available to registered researchers through the UKB data-access protocol. Additional information about registration for access to the data are available at: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. GWAS summary statistics will be submitted to the GWAS catalogue upon publication. The supplementary table is available for downloading at https://osf.io/9s6gk/.