Genome-wide Association and Replication Studies Identified TRHR as an Important Gene for Lean Body Mass

Xiao Gang Liu, Li Jun Tan, Shu Feng Lei, Yong Jun Liu, Hui Shen, Liang Wang, Han Yan, Yan Fang Guo, Dong Hai Xiong, Xiang Ding Chen, Feng Pan, Tie Lin Yang, Yin Ping Zhang, Yan Guo, Nelson L. Tang, Xue Zhen Zhu, Hong Yi Deng, Shawn Levy, Robert R. Recker, Christopher J. PapasianHong Wen Deng

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Abstract

Low lean body mass (LBM) is related to a series of health problems, such as osteoporotic fracture and sarcopenia. Here we report a genome-wide association (GWA) study on LBM variation, by using Affymetrix 500K single-nucleotide polymorphism (SNP) arrays. In the GWA scan, we tested 379,319 eligible SNPs in 1,000 unrelated US whites and found that two SNPs, rs16892496 (p = 7.55 × 10-8) and rs7832552 (p = 7.58 × 10-8), within the thyrotropin-releasing hormone receptor (TRHR) gene were significantly associated with LBM. Subjects carrying unfavorable genotypes at rs16892496 and rs7832552 had, on average, 2.70 and 2.55 kg lower LBM, respectively, compared to those with alternative genotypes. We replicated the significant associations in three independent samples: (1) 1488 unrelated US whites, (2) 2955 Chinese unrelated subjects, and (3) 593 nuclear families comprising 1972 US whites. Meta-analyses of the GWA scan and the replication studies yielded p values of 5.53 × 10-9 for rs16892496 and 3.88 × 10-10 for rs7832552. In addition, we found significant interactions between rs16892496 and polymorphisms of several other genes involved in the hypothalamic-pituitary-thyroid and the growth hormone-insulin-like growth factor-I axes. Results of this study, together with the functional relevance of TRHR in muscle metabolism, support the TRHR gene as an important gene for LBM variation.

Original languageEnglish (US)
Pages (from-to)418-423
Number of pages6
JournalAmerican journal of human genetics
Volume84
Issue number3
DOIs
StatePublished - Mar 13 2009

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All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Liu, X. G., Tan, L. J., Lei, S. F., Liu, Y. J., Shen, H., Wang, L., Yan, H., Guo, Y. F., Xiong, D. H., Chen, X. D., Pan, F., Yang, T. L., Zhang, Y. P., Guo, Y., Tang, N. L., Zhu, X. Z., Deng, H. Y., Levy, S., Recker, R. R., ... Deng, H. W. (2009). Genome-wide Association and Replication Studies Identified TRHR as an Important Gene for Lean Body Mass. American journal of human genetics, 84(3), 418-423. https://doi.org/10.1016/j.ajhg.2009.02.004