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Targeted next generation sequencing of nine osteoporosis-related genes in the Wnt signaling pathway among Chinese postmenopausal women

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Abstract

Purpose

This study aimed to explore the association between low-frequency and rare variants of Wnt signaling genes and postmenopausal osteoporosis (OP) by the next generation sequencing (NGS) technology.

Methods

We performed targeted NGS of nine Wnt signaling genes in 400 Chinese postmenopausal women, including 226 cases with decreased bone mineral density (BMD) and 174 controls with normal values. Proxy External Controls Association Test (ProxECAT) and logistic regression analysis were performed by data from internal cases (n = 226) and Genome Aggregation Database (gnomAD) East Asian controls (n = 9435).

Results

The genomic region of interest (ROI) of 94 functional low-frequency and rare variants was associated with OP risk (P < 0.05). The LGR6 gene was associated significantly with OP risk and BMD measurements (BMD, T-score and Z-score) (adjusted-P < 0.05) after adjusting for confounders. The allele A of rs199693693 (K82N) in LRP6 and G of novel variant 1: 202287949 (R840G) in LGR6 were associated with higher BMD, T-score, and Z-score (all adjusted-P < 0.05). ProxECAT showed that LGR4 was significantly different between the internal cases and the external controls (all adjusted-P < 0.05). Logistic regression analysis revealed that the allele G of rs765778410 (T645A) (OR = 26.16, 95% CI: 4.36–156.95, adjusted-P value = 0.026) in LGR6 and A of rs61370283 (L987M) (OR = 15.39, 95% CI: 2.98–79.55, adjusted-P value = 0.037) in LRP5 were associated with increased risk of postmenopausal OP.

Conclusion

The LGR4 and LGR6 genes and four potential functional rare variants associate with postmenopausal OP risk. These results highlight the significance of rare functional variants in postmenopausal OP genetics and provide new insights into the potential mutations in this field.

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Acknowledgements

The work was supported by the National Natural Science Foundation of China [Grant no. 81573235], the Natural Science Foundation of Hubei Province [Grant no. 2019CFB647 and 2019CFB709], and the Fundamental Research Funds for the Central Universities [Grant no. 2019kfyXKJC003].

Author information

Author notes

  1. These authors contributed equally: Can Li, Qin Huang, Rui Yang, Xiaodong Guo

Authors and Affiliations

  1. MOE Key Lab of Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China

    Can Li, Lailin Tao, Xiaolong Li, Haolong Zhou & Qi Wang

  2. Department of Rehabilitation Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China

    Qin Huang

  3. Department of Health Checkup, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China

    Rui Yang & Junchao Zeng

  4. Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China

    Xiaodong Guo

  5. Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China

    Yu Dai

  6. Wuhan No.1 Hospital, 430030, Wuhan, China

    Yun Zeng

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Contributions

C.L., Q.H., R.Y., X.G., and Q.W. designed the research; C.L., Q.H., R.Y., X.G., Y.D., J.Z., Y.Z., L.T, X.L., and H.Z. conducted the research; C.L. analyzed the data; C.L., Q.H., and R.Y. wrote the draft; all authors read, reviewed, and approved the final paper; Q.W. had primary responsibility for final content.

Corresponding author

Correspondence to Qi Wang.

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Li, C., Huang, Q., Yang, R. et al. Targeted next generation sequencing of nine osteoporosis-related genes in the Wnt signaling pathway among Chinese postmenopausal women. Endocrine 68, 669–678 (2020). https://doi.org/10.1007/s12020-020-02248-x

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