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Association of 3q13.32 variants with hip trochanter and intertrochanter bone mineral density identified by a genome-wide association study

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Abstract

Summary

We performed a GWAS of trochanter and intertrochanter bone mineral density (BMD) in the Framingham Heart Study and replicated in three independent studies. Our results identified one novel locus around the associated variations at chromosomal region 3q13.32 and replicated two loci at chromosomal regions 3p21 and 8q24. Our findings provide useful insights that enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.

Introduction

Hip trochanter (TRO) and intertrochanter (INT) subregions have important clinical relevance to subtrochanteric and intertrochanteric fractures but have rarely been studied by genome-wide association studies (GWASs).

Methods

Aiming to identify genomic loci associated with BMD variation at TRO and INT regions, we performed a GWAS utilizing the Framingham Heart Study (FHS, N = 6,912) as discovery sample and utilized the Women’s Health Initiative (WHI) African-American subsample (N = 845), WHI Hispanic subsample (N = 446), and Omaha osteoporosis study (N = 971), for replication.

Results

Combining the evidence from both the discovery and the replication samples, we identified one novel locus around the associated variations at chromosomal region 3q13.32 (rs1949542, discovery p = 6.16 × 10−8, replication p = 2.86 × 10−4 for INT-BMD; discovery p = 1.35 × 10−7, replication p = 4.16 × 10−4 for TRO-BMD, closest gene RP11-384F7.1). We also replicated two loci at chromosomal regions 3p21 (rs148725943, discovery p = 6.61 × 10−7, replication p = 5.22 × 10−4 for TRO-BMD, closest gene CTNNB1) and 8q24 (rs7839059, discovery p = 2.28 × 10−7, replication p = 1.55 × 10−3 for TRO-BMD, closest gene TNFRSF11B) that were reported previously. We demonstrated that the effects at both 3q13.32 and 3p21 were specific to the TRO, but not to the femoral neck and spine. In contrast, the effect at 8q24 was common to all the sites.

Conclusion

Our findings provide useful insights that enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.

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Acknowledgments

This study was partially supported by the National Natural Science Foundation of China (31571291 and 31100902 to L.Z., 31501026 to Y.F.P., 81460223 to R.H.), the NIH (P50AR055081, R01AG026564, R01AR050496, RC2DE020756, R01AR057049, and R03TW008221 to H.W.D.), the Natural Science Foundation of Jiangsu Province of China (BK20150323 to Y.F.P.), the Franklin D. Dickson/Missouri Endowment and the Edward G. Schlieder Endowment (to H.W.D.), the Startup Funding Project of Soochow University (Q413900214 to L.Z. and Q413900114 to Y.F.P.), and a Project of The Priority Academic Program Development of Jiangsu Higher Education Institutions. Computing service was partially provided by the University of Shanghai for science and technology computing cluster.

The FHS 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 FHS and does not necessarily reflect the opinions or views of the FHS, 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 http://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 Institutes of Health, and the US 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 http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession phs000200.v10.p3.

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    Authors and Affiliations

    1. Department of Epidemiology and Health Statistics, School of Public Health, Medical College of Soochow University, Jiangsu, People’s Republic of China

      Y.-F. Pei & Y.-H. Zhang

    2. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, People’s Republic of China

      Y.-F. Pei, W.-Z. Hu, Y.-H. Zhang, S.-F. Lei & L. Zhang

    3. The Second Affiliated Hospital of Soochow University, Jiangsu, People’s Republic of China

      Z.-G. Xie & L.-B. Li

    4. Inner Mongolia Autonomous Region People’s Hospital, Hohhot, Inner Mongolia, People’s Republic of China

      X.-Y. Wang & R. Hai

    5. Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, 199 Ren-ai Rd., Suzhou City, Jiangsu Province, 215123, People’s Republic of China

      W.-Z. Hu, S.-F. Lei & L. Zhang

    6. Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China

      S. Ran & Y. Lin

    7. Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA

      H. Shen, Q. Tian & H.-W. Deng

    8. Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO, USA

      C. J. Papasian

    9. Center for Bioinformatics and Genomics, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal St., Suite 2001, New Orleans, LA, 70112, USA

      H.-W. Deng

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    Additional information

    Hong-Wen Deng and Lei Zhang jointly supervised this study.

    Yu-Fang Pei and Zong-Gang Xie contributed equally to this work.

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    Pei, YF., Xie, ZG., Wang, XY. et al. Association of 3q13.32 variants with hip trochanter and intertrochanter bone mineral density identified by a genome-wide association study. Osteoporos Int 27, 3343–3354 (2016). https://doi.org/10.1007/s00198-016-3663-y

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