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. Papasian; Hong Wen Deng

doi:10.1016/j.ajhg.2009.02.004

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 language	English (US)
Pages (from-to)	418-423
Number of pages	6
Journal	American Journal of Human Genetics
Volume	84
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2009.02.004
State	Published - Mar 13 2009

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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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

Liu, XG, Tan, LJ, Lei, SF, Liu, YJ, Shen, H, Wang, L, Yan, H, Guo, YF, Xiong, DH, Chen, XD, Pan, F, Yang, TL, Zhang, YP, Guo, Y, Tang, NL, Zhu, XZ, Deng, HY, Levy, S, Recker, RR, Papasian, CJ & Deng, HW 2009, 'Genome-wide Association and Replication Studies Identified TRHR as an Important Gene for Lean Body Mass', American Journal of Human Genetics, vol. 84, no. 3, pp. 418-423. https://doi.org/10.1016/j.ajhg.2009.02.004

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

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.",

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

note = "Funding Information: Investigators of this work were partially supported by grants from NIH (R01 AR050496-01, R21 AG027110, R01 AG026564, R21 AA015973, and P50 AR055081).The study also benefited from grants from National Science Foundation of China, Huo Ying Dong Education Foundation, Hunan Province, Xi'an Jiaotong University, and the Ministry of Education of China. The authors declare that they have no conflict of interest. ",

year = "2009",

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doi = "10.1016/j.ajhg.2009.02.004",

language = "English (US)",

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T1 - Genome-wide Association and Replication Studies Identified TRHR as an Important Gene for Lean Body Mass

AU - Liu, Xiao Gang

AU - Tan, Li Jun

AU - Lei, Shu Feng

AU - Liu, Yong Jun

AU - Shen, Hui

AU - Wang, Liang

AU - Yan, Han

AU - Guo, Yan Fang

AU - Xiong, Dong Hai

AU - Chen, Xiang Ding

AU - Pan, Feng

AU - Yang, Tie Lin

AU - Zhang, Yin Ping

AU - Guo, Yan

AU - Tang, Nelson L.

AU - Zhu, Xue Zhen

AU - Deng, Hong Yi

AU - Levy, Shawn

AU - Recker, Robert R.

AU - Papasian, Christopher J.

AU - Deng, Hong Wen

N1 - Funding Information: Investigators of this work were partially supported by grants from NIH (R01 AR050496-01, R21 AG027110, R01 AG026564, R21 AA015973, and P50 AR055081).The study also benefited from grants from National Science Foundation of China, Huo Ying Dong Education Foundation, Hunan Province, Xi'an Jiaotong University, and the Ministry of Education of China. The authors declare that they have no conflict of interest.

PY - 2009/3/13

Y1 - 2009/3/13

N2 - 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.

AB - 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.

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

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