Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Identification of novel genetic variants associated with longitudinal changes in bone mineral density (#313)

Krisel De Dios 1 , Ngoc Huynh 1 , John P Kemp 2 3 , Thach Tran 1 , Lan T Ho-Pham 4 , Tuan V Nguyen 1 5
  1. School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
  2. Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
  3. Musculoskeletal Research Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom
  4. Saigon Precision Medicine Research Center, Ho Chi Minh City, Vietnam
  5. School of Population Health, University of New South Wales, Sydney, NSW, Australia

Objective

While it is well documented that hereditary factors influence changes in bone mineral density (BMD), the precise genetic variants linked to longitudinal BMD change, particularly bone loss, remain unidentified. To fill this knowledge gap, we undertook a genome-wide association study (GWAS) to identify loci associated with BMD change.

Methods

This study involved 2345 men and women (average baseline age of 54 years) who were part of the Vietnam Osteoporosis Study (VOS) with two to four BMD measurements. BMD at the total hip, femoral neck and lumbar spine was measured using DXA (Hologic Horizon) between 2015 and 2020. The rate of BMD change was determined using a linear mixed-effects regression model. Our genotyping analysis employed the Illumina Infinium assay platform, specifically the Global Screen Array microchip containing over 700,000 single nucleotide polymorphisms (SNPs). We conducted a mixed linear model-based GWAS analysis, adjusting for age and sex.

Results

Several genome-wide significant associations (P<5×10-8) were identified in the ARHGAP6 gene locus (associated with FNBMD) and novel transcript ENSG00000267175 (total hip BMD). For LSBMD, only suggestive associations (P<5×10-6) were found at the following loci: EMX1, LINC02492, SH3TC2-DT, DMD. Other than the ARHGAP6 and DMD loci, our GWAS findings are novel and not previously reported in cross-sectional areal BMD GWAS.

Conclusion

We identified 5 new genome-wide significant loci that are associated with BMD change at the total hip and femoral neck. This finding hints at the existence of overlapping biological pathways from single BMD measurements; and distinct pathways linked to age-related bone loss. Further work to understand the biological mechanism of the identified genetic variants may uncover novel personalised diagnostic markers and therapeutic targets for osteoporosis.

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