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

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.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2009; 84(3):418-23. DOI: 10.1016/j.ajhg.2009.02.004
Source: PubMed


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.

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Available from: Shawn Levy, Sep 12, 2014
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    • "Genome-wide association studies of BMD, osteoporosis, and osteoporotic fracture have also been reported (Urano et al., 2010, 2012; Richards et al., 2012). Recently, GWA studies have also identified common genetic variants associated with lean body mass (Liu et al., 2009; Hai et al., 2012; Guo et al., 2013). To the best of our knowledge, this is the first large-scale association study for lean body mass variation in the Japanese population. "
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    • "Molecular genetic studies have identified a series of candidate genes for low BMI including a thyrotropin-releasing hormone (TRH) receptor polymorphism [7], the Ser23 allele of the serotonin 2C receptor [8], a genetic variant on chromosome 16p11.2 [9] and a copy number variant identified as gremlin1 [10]. "
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    ABSTRACT: The low body mass index (BMI) phenotype of less than 18.5 has been linked to medical and psychological morbidity as well as increased mortality risk. Although genetic factors have been shown to influence BMI across the entire BMI, the contribution of genetic factors to the low BMI phenotype is unclear. We hypothesized genetic factors would contribute to risk of a low BMI phenotype. To test this hypothesis, we conducted a genealogy data analysis using height and weight measurements from driver's license data from the Utah Population Data Base. The Genealogical Index of Familiality (GIF) test and relative risk in relatives were used to examine evidence for excess relatedness among individuals with the low BMI phenotype. The overall GIF test for excess relatedness in the low BMI phenotype showed a significant excess over expected (GIF 4.47 for all cases versus 4.10 for controls, overall empirical p-value<0.001). The significant excess relatedness was still observed when close relationships were ignored, supporting a specific genetic contribution rather than only a family environmental effect. This study supports a specific genetic contribution in the risk for the low BMI phenotype. Better understanding of the genetic contribution to low BMI holds promise for weight regulation and potentially for novel strategies in the treatment of leanness and obesity.
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    • "In a recent GWA study examining 379,319 SNPs in a cohort of US unrelated whites (492 men, 481 women, mean age 50 years) (Liu et al., 2009), the authors associated with LBM two SNPs within the thyrotropin-releasing hormone receptor (TRHR) gene, rs16892496 and rs7832552. Individuals carrying 'unfavorable' rs16892496 and rs7832552 genotypes showed lower LBM respectively, compared to the other genotypes. "
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    ABSTRACT: Persons aged 80 years and older are the fastest growing segment of the population. As more individuals live longer, we should try to understand the mechanisms involved in healthy ageing and preserving functional independence in later life. In elderly people, functional independence is directly dependent on physical fitness, and ageing is inevitably associated with the declining functions of systems and organs (heart, lungs, blood vessels, skeletal muscles) that determine physical fitness. Thus, age-related diminished physical fitness contributes to the development of sarcopenia, frailty or disability, all of which severely deteriorate independent living and thus quality of life. Ageing is a complex process involving many variables that interact with one another, including - besides lifestyle factors or chronic diseases - genetics. Thus, several studies have examined the contribution of genetic endowment to a decline in physical fitness and subsequent loss of independence in later life. In this review, we compile information, including data from heritability, candidate-gene association, linkage and genome-wide association studies, on genetic factors that could influence physical fitness in the elderly.
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