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A longitudinal genome-wide association study of bone mineral density mean and variability in the UK Biobank

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Abstract

Summary

Bone mineral density (BMD) is an essential predictor of osteoporosis and fracture. We conducted a genome-wide trajectory analysis of BMD and analyzed the BMD change.

Purpose

This study aimed to identify the genetic architecture and potential biomarkers of BMD.

Methods

Our analysis included 141,261 white participants from the UK Biobank with heel BMD phenotype data. We used a genome-wide trajectory analysis tool, TrajGWAS, to conduct a genome-wide association study (GWAS) of BMD. Then, we validated our findings in previously reported BMD genetic associations and performed replication analysis in the Asian participants. Finally, gene-set enrichment analysis (GSEA) of the identified candidate genes was conducted using the FUMA platform.

Results

A total of 52 genes associated with BMD trajectory mean were identified, of which the top three significant genes were WNT16 (P = 1.31 × 10−126), FAM3C (P = 4.18 × 10−108), and CPED1 (P = 8.48 × 10−106). In addition, 114 genes associated with BMD within-subject variability were also identified, such as AC092079.1 (P = 2.72 × 10−13) and RGS7 (P = 4.72 × 10−10). The associations for these candidate genes were confirmed in the previous GWASs and replicated successfully in the Asian participants. GSEA results of BMD change identified multiple GO terms related to skeletal development, such as SKELETAL SYSTEM DEVELOPMENT (Padjusted = 2.45 × 10−3) and REGULATION OF OSSIFICATION (Padjusted = 2.45 × 10−3). KEGG enrichment analysis showed that these genes were mainly enriched in WNT SIGNALING PATHWAY.

Conclusions

Our findings indicated that the CPED1-WNT16-FAM3C locus plays a significant role in BMD mean trajectories and identified several novel candidate genes contributing to BMD within-subject variability, facilitating the understanding of the genetic architecture of BMD.

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Data availability

The UK Biobank data are available through the UK Biobank Access Management System (https://www.ukbiobank.ac.uk/). We will return the derived data fields following UK Biobank policy; in due course, they will be available through the UK Biobank Access Management System.

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Funding

This work was supported by the National Natural Scientific Foundation of China [81922059]; the Natural Science Basic Research Plan in Shaanxi Province of China [2021JCW-08].

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Author notes

  1. Dan He and Huan Liu contributed equally to this work as the first authors.

Authors and Affiliations

  1. Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi’an Jiaotong University, Xi’an, 710061, China

    Dan He, Huan Liu, Wenming Wei, Yijing Zhao, Qingqing Cai, Sirong Shi, Xiaoge Chu, Xiaoyue Qin, Na Zhang & Feng Zhang

  2. Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China

    Dan He, Huan Liu, Wenming Wei, Yijing Zhao, Qingqing Cai, Sirong Shi, Xiaoge Chu, Xiaoyue Qin, Na Zhang & Feng Zhang

  3. Key Laboratory for Disease Prevention and Control and Health Promotion of Shaanxi Province, Xi’an Jiaotong University, Xi’an, China

    Dan He, Huan Liu, Wenming Wei, Yijing Zhao, Qingqing Cai, Sirong Shi, Xiaoge Chu, Xiaoyue Qin, Na Zhang & Feng Zhang

  4. School of Public Health, Xi’an Jiaotong University Health Science Center, No.76 Yan Ta West Road, Xi’an, 710061, China

    Dan He, Huan Liu, Wenming Wei, Yijing Zhao, Qingqing Cai, Sirong Shi, Xiaoge Chu, Xiaoyue Qin, Na Zhang & Feng Zhang

  5. Department of Joint Surgery, HongHui Hospital, Xi’an Jiaotong University, Xi’an, 710054, Shanxi, China

    Peng Xu

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  1. Dan He
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  2. Huan Liu
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Correspondence to Peng Xu or Feng Zhang.

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Dan He, Huan Liu, Wenming Wei, Yijing Zhao, Qingqing Cai, Sirong Shi, Xiaoge Chu, Xiaoyue Qin, Na Zhang, Peng Xu, Feng Zhang declare that they have no conflict of interest.

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He, D., Liu, H., Wei, W. et al. A longitudinal genome-wide association study of bone mineral density mean and variability in the UK Biobank. Osteoporos Int 34, 1907–1916 (2023). https://doi.org/10.1007/s00198-023-06852-1

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