Genome-wide association and replication studies identified TRHR as an important gene for lean body mass.
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 x 10(-8)) and rs7832552 (p = 7.58 x 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 x 10(-9) for rs16892496 and 3.88 x 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.
Liu
Xiao-Gang
XG
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an Shaanxi, P R China.
Tan
Li-Jun
LJ
Lei
Shu-Feng
SF
Liu
Yong-Jun
YJ
Shen
Hui
H
Wang
Liang
L
Yan
Han
H
Guo
Yan-Fang
YF
Xiong
Dong-Hai
DH
Chen
Xiang-Ding
XD
Pan
Feng
F
Yang
Tie-Lin
TL
Zhang
Yin-Ping
YP
Guo
Yan
Y
Tang
Nelson L
NL
Zhu
Xue-Zhen
XZ
Deng
Hong-Yi
HY
Levy
Shawn
S
Recker
Robert R
RR
Papasian
Christopher J
CJ
Deng
Hong-Wen
HW
D000328:Adult; D000368:Aged; D001213:Asian; D001823:Body Composition / Q000235:genetics*; D001835:Body Weight / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D013851:Thinness; D044465:White People
D018025:Receptors, Thyrotropin-Releasing Hormone