Three pleiotropic loci associated with bone mineral density and lean body mass

Abstract

Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and replication sample, we identified three genomic loci at the genome-wide significance level (p < 5.0 × 10–8): 2p23.2 (lead SNP rs4477866, discovery p = 3.47 × 10–8, replication p = 1.03 × 10–4), 16q12.2 (rs1421085, discovery p = 2.04 × 10–9, replication p = 6.47 × 10–14) and 18q21.32 (rs11152213, discovery p = 3.47 × 10–8, replication p = 6.69 × 10–6). Our findings not only provide useful insights into lean mass and bone mass development, but also enhance our understanding of the potential genetic correlation between BMD and LBM.

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Fig. 1
Fig. 2

Data availability

Summary results are available upon request to the corresponding author.

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Acknowledgements

We appreciate all the volunteers who participated in this study. This analysis of the UK Biobank sample was conducted using the UK Biobank resource under application number 41542. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract no. N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the Framingham Whole Body and Regional Dual X-ray Absorptiometry (DXA) dataset was provided by NIH grants R01 AR/AG 41398. The datasets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession phs000342.v14.p10. The WHI program is funded by the National Heart, Lung, and Blood Institute, National 20 Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women’s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278. The datasets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession phs000200.v10.p3.

Funding

This study was partially supported by the support from the national natural science foundation of China (31501026 and 31771417 to YFP, 31571291 to LZ), the Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University (201810285048Z), the NIH (R01 AR069055, U19 AG055373, R01 MH104680, R01 AR059781 and P20 GM109036), the Franklin D. Dickson/Missouri Endowment and the Edward G. Schlieder Endowment, and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu higher education institutions. The numerical calculations in this paper have been done on the supercomputing system of the National Supercomputing Center in Changsha. The funders had no role in study design, data collection and analysis, results interpretation or preparation of the manuscript.

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LZ and YFP designed the study. LZ, YFP, YXZ, SSZ, SR, HS, QT, RH, and HWD collected the data. YFP and LZ analyzed the data. YXZ, SSZ, SR, YL, HZ, and XLY performed the literature search. YXZ, SSZ, SR, YL, HZ, XLY, HWD, YFP, and LZ interpreted the data. YXZ, SSZ, and SR generated the figures. YXZ, SSZ, and SR drafted the early version of the manuscript. LZ, YFP supervised the study. All authors were involved in writing the paper and had final approval of the submitted and published versions.

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Correspondence to Hong-Wen Deng or Lei Zhang or Yu-Fang Pei.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Zhang, YX., Zhang, SS., Ran, S. et al. Three pleiotropic loci associated with bone mineral density and lean body mass. Mol Genet Genomics 296, 55–65 (2021). https://doi.org/10.1007/s00438-020-01724-3

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Keywords

  • Bivariate genome-wide association study
  • Pleiotropic effect
  • Sarcopenia
  • Osteoporosis