The genetic architecture of appendicular lean mass characterized by association analysis in the UK Biobank study

Pei, Yu‐Fang; Liu, Yaozhong; Yang, Xiaolin; Zhang, Lei; Feng, Guoliang; Wei, Xin‐Tong

doi:10.1038/s42003-020-01334-0

Cited by 151 publications

(126 citation statements)

References 61 publications

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“…In this study, a total of 156 potential ALM-associated SNPs mapping to 15 chromosomes were identified by cFDR (Supplementary Figure 2 and Supplementary Table 3). We compared the SNPs found to be significant by cFDR with previous GWAS findings (Supplementary Table 4) and the latest findings by Pei et al (10). Eight LM-associated SNPs (rs12284933, rs12741884, rs3765350, rs6591341, rs6726821, rs754388, rs917727 and rs9525638) reported by previous GWASs were replicated by cFDR (SNPs marked * in Supplementary Table 3), 66 ALM SNPs identified as significant by cFDR (SNPs marked ** in Supplementary Table 3) exhibited high LD with previouslyconfirmed LM-associated SNPs.…”

Section: Novel Potential Alm-associated Snps Identified By Cfdrmentioning

confidence: 99%

“…For example, loci are present in TRHR (5), GLYAT (6), PRDM16 (7) and TNRC6B (8). Furthermore, the latest large-scale GWAS has just identified and replicated five loci strongly associated with LM at a genome-wide level of significance (9), and a recent ALM GWAS study identified 1059 conditionally independent variants from 799 loci with a genome-wide significance level (p <5 × 10 −9 ) using the UKB cohort (10). These findings help us better understand the genetic background of sarcopenia, but because of the high heritability of LM, the current findings are extremely limited, a missing heritability is evident.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Identification of Novel Potential Variants for Appendicular Lean Mass by Leveraging Pleiotropy With Bone Mineral Density

Peng

Liu

et al. 2021

Front. Immunol.

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Strong relationships have been found between appendicular lean mass (ALM) and bone mineral density (BMD). It may be due to a shared genetic basis, termed pleiotropy. By leveraging the pleiotropy with BMD, the aim of this study was to detect more potential genetic variants for ALM. Using the conditional false discovery rate (cFDR) methodology, a combined analysis of the summary statistics of two large independent genome wide association studies (GWAS) of ALM (n = 73,420) and BMD (n = 10,414) was conducted. Strong pleiotropic enrichment and 26 novel potential pleiotropic SNPs were found for ALM and BMD. We identified 156 SNPs for ALM (cFDR <0.05), of which 74 were replicates of previous GWASs and 82 were novel SNPs potentially-associated with ALM. Eleven genes annotated by 31 novel SNPs (13 pleiotropic and 18 ALM specific) were partially validated in a gene expression assay. Functional enrichment analysis indicated that genes corresponding to the novel potential SNPs were enriched in GO terms and/or KEGG pathways that played important roles in muscle development and/or BMD metabolism (adjP <0.05). In protein–protein interaction analysis, rich interactions were demonstrated among the proteins produced by the corresponding genes. In conclusion, the present study, as in other recent studies we have conducted, demonstrated superior efficiency and reliability of the cFDR methodology for enhanced detection of trait-associated genetic variants. Our findings shed novel insight into the genetic variability of ALM in addition to the shared genetic basis underlying ALM and BMD.

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Section: Novel Potential Alm-associated Snps Identified By Cfdrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced Identification of Novel Potential Variants for Appendicular Lean Mass by Leveraging Pleiotropy With Bone Mineral Density

Peng

Liu

et al. 2021

Front. Immunol.

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“…The GRS deployed by Li et al explains less than 1% of the heritability of lean mass and did not correlate with lean mass in POUNDS lost study participants 13,14 . A more recent study identified 1059 SNPs at 799 loci, associated with BIA‐measured appendicular lean mass in both sexes, adjusted for covariates including appendicular fat mass and age 12 . Together, these explain ~15.5% of the heritability of appendicular lean mass (which correlates with total lean mass) 12 .…”

mentioning

confidence: 95%

“…A more recent study identified 1059 SNPs at 799 loci, associated with BIA‐measured appendicular lean mass in both sexes, adjusted for covariates including appendicular fat mass and age 12 . Together, these explain ~15.5% of the heritability of appendicular lean mass (which correlates with total lean mass) 12 . These variants can potentially be used to investigate whether genetically determined appendicular lean mass and/or skeletal muscle mass is causally associated with response to low‐fat diet through Mendelian randomization (MR) analyses.…”

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confidence: 99%

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Genetically determined lean mass and dietary response

Dash

Paterson

2020

Diabetes Obesity Metabolism

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Weight loss attenuates many obesity‐related co‐morbidities, but is difficult to sustain with dietary change. Dietary adherence, not macronutrient composition, is a better predictor of weight loss. Weight loss‐induced endocrine changes promote food intake and increase energy efficiency, contributing to the difficulty with dietary adherence and weight regain. Macronutrient preference is partly genetically determined, suggesting that personalized dietary interventions might be more successful. In this issue, Li et al. report that a genetic risk score comprising the cumulative weighted effects of variants previously associated with increased lean mass is associated with increased satiety and weight loss 6 months after initiating a low‐ but not a high‐fat diet. The effects were attenuated by 2 years. These findings suggest that genetic variants may influence response to specific diet. Further studies are necessary to assess whether genetically determined lean mass is causally associated with dietary response. Significant progress has recently been made in identifying additional genetic determinants of lean mass, which will enable such investigations and potentially inform future nutritional studies.

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Causal relationship between lipid profile and muscle atrophy: A bi‐directional Mendelian randomization study

Chen,

Gao,

Fang

et al. 2023

Anim Models and Exp Med

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BackgroundThe aim of this study was to analyze the bi‐directional causal relationship between lipid profile and characteristics related to muscle atrophy by using a bi‐directional Mendelian randomization (MR) analysis.MethodsThe appendicular lean mass (ALM), whole body fat‐free mass (WBFFM) and trunk fat‐free mass (TFFM) were used as genome‐wide association study (GWAS) data for evaluating muscle mass; the usual walking pace (UWP) and low grip strength (LGS) were used as GWAS data for evaluating muscle strength; and the triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), apolipoprotein A‐1 (Apo A‐1), and apolipoprotein B (Apo B) were used as GWAS data for evaluating lipid profile. For specific investigations, we mainly employed inverse variance weighting for causal estimation and MR‐Egger for pleiotropy analysis.ResultsMR results showed that the lipid profile predicted by genetic variants was negatively correlated with muscle mass, positively correlated with UWP, and was not causally correlated with LGS. On the other hand, the muscle mass predicted by genetic variants was negatively correlated with lipid profile, the UWP predicted by genetic variants was mainly positively correlated with lipid profile, while the LGS predicted by genetic variants had no relevant causal relationship with lipid profile.ConclusionsFindings of this MR analysis suggest that hyperlipidemia may affect muscle mass and lead to muscle atrophy, but has no significant effect on muscle strength. On the other hand, increased muscle mass may reduce the incidence of dyslipidemia.

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The genetic architecture of appendicular lean mass characterized by association analysis in the UK Biobank study

Cited by 151 publications

References 61 publications

Enhanced Identification of Novel Potential Variants for Appendicular Lean Mass by Leveraging Pleiotropy With Bone Mineral Density

Enhanced Identification of Novel Potential Variants for Appendicular Lean Mass by Leveraging Pleiotropy With Bone Mineral Density

Genetically determined lean mass and dietary response

Causal relationship between lipid profile and muscle atrophy: A bi‐directional Mendelian randomization study

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