Poster Presentation GENEMAPPERS 2024

Identifying novel vertebral development factors through UK Biobank driven genetic and body imaging analysis (#98)

Jiru Han 1 2 , Zhuopin Sun 1 2 , Liam Fearnley 1 2 , Edwina McGlinn 3 , Melanie Bahlo 1 2
  1. Department of Medical Biology, The University of Melbourne, Melbourne, Parkville, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville, VICTORIA, Australia
  3. Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia

Evolution of the development of the human axial skeleton has been proposed to be driven by genetic factors. Throughout evolution, the spine became more regionalised and developed heterogeneous anatomical characteristics for specialised functions. Despite knowledge of the role of genetic factors such as the Hox genes, in regulating the development of the vertebral column, limited research has been conducted on large population datasets that could reveal the complex genetic architecture underlying it. 

To explore the full scope of the topic, we aim to combine genetic and image analysis to investigate the genetic influence on vertebral anatomical variations in the UK Biobank (UKB). We first identified 51 candidate genes related to vertebral development, such as increased/decreased thoracic and lumbar vertebrae number, which were compiled from the Human Phenotype Ontology and the Mouse Genome Informatics phenotype databases, along with a novel gene, Nr6A1, identified in the previous mouse studies1. These candidate genes showed phenotypic variation with functionally deleterious genetic variation. Using the AstraZeneca PheWAS (https://azphewas.com), we were able to further refine our anlaysis to six rare variants (MAF <0.01) that showed an association with increased or decreased sitting height, a plausible surrogate marker for an extra and fewer vertebrae. To visualise the complete thoracic and lumbar spines, we trained and implemented a self-supervised deep learning model2 to align the Dual-energy X-ray Absorptiometry and whole-body Dixon Magnetic Resonance data and annotated the matched images to assess the spine anatomy.

Our results showed that individuals with these variants exhibited enriched vertebral and rib anomalies (numeric variations and transitional vertebrae) in GPC3, GDF11, Nr6A1, and VRTN variants with incomplete penetrance and phenotypic heterogeneity. The observed enrichment of spine anatomical anomalies suggests that these genes play a role in regulating vertebral development, potentially impacting human skeletal evolution and related pathologies, via less deleterious genetic variation.