Genome-Wide Association Study Identified Copy Number Variants Important for Appendicular Lean Mass

Ran, Shu; Liu, Yongjun; Zhang, Lei; Pei, Yu‐Fang; Yang, Tie‐Lin; Hai, Rong; Han, Yingying; Lin, Yong; Tian, Qing; Deng, Hong−Wen

doi:10.1371/journal.pone.0089776

Cited by 14 publications

(8 citation statements)

References 36 publications

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“…However, thus far, genome-wide association studies (GWAS) have implicated fewer than a dozen genes, explaining a small fraction of this heritability 9; 10 . Limited sample size in early studies [11][12][13][14][15] and the effects of confounders such as subject age 9 , size of the skeleton and lean mass components (non-fat organs and tissues, heterogeneity of muscle fibers) have hindered detection of genes. The UK Biobank is a resource of demographic, phenotypic and genotypic data collected on ~500,000 individuals 16 .…”

Section: Introductionmentioning

confidence: 99%

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Cordero

Gonzales

Parker

et al. 2019

The American Journal of Human Genetics

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Muscle bulk in adult healthy humans is highly variable even after accounting for height, age and sex. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 85,750 middle-age (38-49 years) individuals from the UK Biobank (UKB) we found 182 loci associated with ALM (P<5x10-8). We replicated associations for 78% of these loci (P<5x10-8) with ALM in a population of 181,862 elderly (60-74 years) individuals from UKB. We also conducted a GWAS on hindlimb skeletal muscle mass of 1,867 mice from an advanced intercross between two inbred strains (LG/J and SM/J) which identified 23 quantitative trait loci. 38 positional candidates distributed across 5 loci overlapped between the two species. In vitro studies of positional candidates confirmed CPNE1 and STC2 as modifiers of myogenesis. Collectively, these findings shed light on the genetics of muscle mass variability in humans and identify targets for the development of interventions for treatment of muscle loss. The overlapping results between humans and the mouse model GWAS point to shared genetic mechanisms across species.

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Section: Introductionmentioning

confidence: 99%

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Cordero

Gonzales

Parker

et al. 2019

The American Journal of Human Genetics

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“…These associations were replicated in three independent samples. Subsequently, several reports have identified the SNPs and genes that are related to the low lean body mass phenotype (Table 3) [89][90][91][92][93].…”

Section: Gwas Related To Osteoporosis and Osteoporotic Fracturesmentioning

confidence: 99%

Recent genetic discoveries in osteoporosis, sarcopenia and obesity [Review]

Urano

Inoue

2015

Endocr J

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Abstract. Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and an increased susceptibility to fractures. Evidence from genetic studies indicates that BMD, a complex quantitative trait with a normal distribution, is genetically controlled. Genome-wide association studies (GWAS) as well as studies using candidate gene approaches have identified single-nucleotide polymorphisms (SNPs) that are associated with BMD, osteoporosis and osteoporotic fractures. These SNPs have been mapped close to or within genes including those encoding WNT/β-catenin signaling proteins. Understanding the genetics of osteoporosis will help to identify novel candidates for diagnostic and therapeutic targets. Genetic factors are also important for the development of sarcopenia, which is characterized by a loss of lean body mass, and obesity, which is characterized by high fat mass. Hence, in this review, we discuss the genetic factors, identified by genetic studies, which regulate the body components related to osteoporosis, sarcopenia, and obesity.

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“…Because of this important advantage, APLM is currently widely used in assessment of a sarcopenic status of an individual 14 as well as in variety of the genetic studies, for example. 15,16 We used a large sample of middle-aged UK female twins, who were assessed using whole body DXA, metabolomic (MTB) screening and genome-wide association scans imputed to 2.5 million variants. In addition, since we were interested in accurate estimation of common and variable-specific genetic and environmental effects on LBM and its associated metabolites, we also implemented a newly developed modification of bivariate analysis, reported here for the first time.…”

Section: Introductionmentioning

confidence: 99%

Genomics and metabolomics of muscular mass in a community-based sample of UK females

et al. 2015

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The contribution of specific molecular-genetic factors to muscle mass variation and sarcopenia remains largely unknown. To identify endogenous molecules and specific genetic factors associated with appendicular lean mass (APLM) in the general population, cross-sectional data from the TwinsUK Adult Twin Registry were used. Non-targeted mass spec-based metabolomic profiling was performed on plasma of 3953 females (mostly dizygotic and monozygotic twins). APLM was measured using dualenergy X-ray absorptiometry (DXA) and genotyping was genome-wide (GWAS). Specific metabolites were used as intermediate phenotypes in the identification of single-nucleotide polymorphisms associated with APLM using GWAS. In all, 162 metabolites were found significantly correlated with APLM, and explained 17.4% of its variation. However, the top three of them (unidentified substance X12063, urate, and mannose) explained 11.1% (P ≤ 9.25 × 10 − 26 ) so each was subjected to GWAS. Each metabolite showed highly significant (P ≤ 9.28 × 10 − 46 ) associations with genetic variants in the corresponding genomic regions. Mendelian randomization using these SNPs found no evidence for a direct causal effect of these metabolites on APLM. However, using a new software platform for bivariate analysis we showed that shared genetic factors contribute significantly (P ≤ 4.31 × 10 − 43 ) to variance in both the metabolites and APLM -independent of the effect of the associated SNPs. There are several metabolites, having a clear pattern of genetic inheritance, which are highly significantly associated with APLM and may provide a cheap and readily accessible biomarker of muscle mass. However, the mechanism by which the genetic factor influences muscle mass remains to be discovered.

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Genome-Wide Association Study Identified Copy Number Variants Important for Appendicular Lean Mass

Cited by 14 publications

References 36 publications

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Recent genetic discoveries in osteoporosis, sarcopenia and obesity [Review]

Genomics and metabolomics of muscular mass in a community-based sample of UK females

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