Dataset Information

Disentangling the genetics of lean mass.

ABSTRACT: Background:Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives:To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods:We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results:Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions:In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

SUBMITTER: Karasik D

PROVIDER: S-EPMC6500901 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Disentangling the genetics of lean mass.

Karasik David D Zillikens M Carola MC Hsu Yi-Hsiang YH Aghdassi Ali A Akesson Kristina K Amin Najaf N Barroso Inês I Bennett David A DA Bertram Lars L Bochud Murielle M Borecki Ingrid B IB Broer Linda L Buchman Aron S AS Byberg Liisa L Campbell Harry H Campos-Obando Natalia N Cauley Jane A JA Cawthon Peggy M PM Chambers John C JC Chen Zhao Z Cho Nam H NH Choi Hyung Jin HJ Chou Wen-Chi WC Cummings Steven R SR de Groot Lisette C P G M LCPGM De Jager Phillip L PL Demuth Ilja I Diatchenko Luda L Econs Michael J MJ Eiriksdottir Gudny G Enneman Anke W AW Eriksson Joel J Eriksson Johan G JG Estrada Karol K Evans Daniel S DS Feitosa Mary F MF Fu Mao M Gieger Christian C Grallert Harald H Gudnason Vilmundur V Lenore Launer J LJ Hayward Caroline C Hofman Albert A Homuth Georg G Huffman Kim M KM Husted Lise B LB Illig Thomas T Ingelsson Erik E Ittermann Till T Jansson John-Olov JO Johnson Toby T Biffar Reiner R Jordan Joanne M JM Jula Antti A Karlsson Magnus M Khaw Kay-Tee KT Kilpeläinen Tuomas O TO Klopp Norman N Kloth Jacqueline S L JSL Koller Daniel L DL Kooner Jaspal S JS Kraus William E WE Kritchevsky Stephen S Kutalik Zoltán Z Kuulasmaa Teemu T Kuusisto Johanna J Laakso Markku M Lahti Jari J Lang Thomas T Langdahl Bente L BL Lerch Markus M MM Lewis Joshua R JR Lill Christina C Lind Lars L Lindgren Cecilia C Liu Yongmei Y Livshits Gregory G Ljunggren Östen Ö Loos Ruth J F RJF Lorentzon Mattias M Luan Jian'an J Luben Robert N RN Malkin Ida I McGuigan Fiona E FE Medina-Gomez Carolina C Meitinger Thomas T Melhus Håkan H Mellström Dan D Michaëlsson Karl K Mitchell Braxton D BD Morris Andrew P AP Mosekilde Leif L Nethander Maria M Newman Anne B AB O'Connell Jeffery R JR Oostra Ben A BA Orwoll Eric S ES Palotie Aarno A Peacock Munro M Perola Markus M Peters Annette A Prince Richard L RL Psaty Bruce M BM Räikkönen Katri K Ralston Stuart H SH Ripatti Samuli S Rivadeneira Fernando F Robbins John A JA Rotter Jerome I JI Rudan Igor I Salomaa Veikko V Satterfield Suzanne S Schipf Sabine S Shin Chan Soo CS Smith Albert V AV Smith Shad B SB Soranzo Nicole N Spector Timothy D TD Stancáková Alena A Stefansson Kari K Steinhagen-Thiessen Elisabeth E Stolk Lisette L Streeten Elizabeth A EA Styrkarsdottir Unnur U Swart Karin M A KMA Thompson Patricia P Thomson Cynthia A CA Thorleifsson Gudmar G Thorsteinsdottir Unnur U Tikkanen Emmi E Tranah Gregory J GJ Uitterlinden André G AG van Duijn Cornelia M CM van Schoor Natasja M NM Vandenput Liesbeth L Vollenweider Peter P Völzke Henry H Wactawski-Wende Jean J Walker Mark M J Wareham Nicholas N Waterworth Dawn D Weedon Michael N MN Wichmann H-Erich HE Widen Elisabeth E Williams Frances M K FMK Wilson James F JF Wright Nicole C NC Yerges-Armstrong Laura M LM Yu Lei L Zhang Weihua W Zhao Jing Hua JH Zhou Yanhua Y Nielson Carrie M CM Harris Tamara B TB Demissie Serkalem S Kiel Douglas P DP Ohlsson Claes C

The American journal of clinical nutrition 20190201 2

<h4>Background</h4>Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.<h4>Objectives</h4>To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.<h4>Methods</h4>We performed genome-wide associat ...[more]

PMID: 30721968

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Project description:BackgroundLittle is known about the association of changes in two body components, muscle and fat mass, with the risk of cardiovascular disease (CVD) among young adults. We investigated the association of changes in predicted lean body mass index (LBMI), appendicular skeletal muscle mass index (ASMI), and body fat mass index (BFMI) with the development of CVD among young adults.MethodsThis nationwide, population-based cohort study included 3 727 738 young adults [2 406 046 (64.5%) men and 1 321 692 (35.5%) women] aged 20-39 years without a previous history of CVD who underwent two health screening examinations during 2009-2010 and 2011-2012. Using validated and robust prediction equations, we calculated the changes in predicted LBMI, ASMI, and BFMI from the first to the second examinations.ResultsThe mean (SD) age was 32.2 (4.9) years, and 2 406 046 (64.5%) of the participants were men. A total of 23 344 CVD events were detected during 22 257 632 person-years of follow-up. Each 1 kg/m2 increase in predicted LBMI and ASMI change was associated with a reduced risk of CVD among men [adjusted hazard ratio (aHR): 0.86, 95% confidence interval (CI) 0.82-0.91; aHR: 0.76, 95% CI 0.69-0.82, respectively] and women (aHR: 0.77, 95% CI 0.63-0.95; aHR: 0.75, 95% CI 0.59-0.96). Each 1 kg/m2 increase in predicted BFMI change was associated with an increased risk of CVD among men (aHR: 1.16, 95% CI 1.10-1.22) and women (aHR: 1.32, 95% CI 1.06-1.65). In both sexes, decreases in predicted LBMI and ASMI were associated with greater CVD risk, and decreased predicted BFMI was associated with a reduced CVD risk. Those who maintained their BMI between -1 and +1 kg/m2 also had a decreased risk of CVD per 1 kg/m2 increase in predicted LBMI and ASMI change among men (aHR: 0.86, 95% CI 0.80-0.92; aHR: 0.85, 95% CI 0.76-0.95) and women (aHR: 0.62, 95% CI 0.47-0.83; aHR: 0.59, 95% CI 0.44-0.80) and had a greater risk of CVD per 1 kg/m2 increase in predicted BFMI change among men (aHR: 1.17, 95% CI 1.10-1.25) and women (aHR: 1.64, 95% CI 1.20-2.23). Regardless of changes in weight, such as from normal to obese or vice versa, these results were consistent.ConclusionsAmong young adults, increased predicted muscle mass or decreased predicted fat mass were associated with a reduced risk of development of CVD. Decreased predicted muscle mass or increased predicted fat mass were associated with an elevated risk of development of CVD.

Project description:BackgroundLow lean body mass is the most important predictor of sarcopenia with strong genetic background. The aim of this study was to uncover genetic factors underlying lean mass development.Materials and methodsWe performed a genome-wide association study (GWAS) of fat-adjusted leg lean mass in the Framingham Heart Study (FHS, N = 6587), and replicated in the Women's Health Initiative-African American sub-sample (WHI-AA, N = 847) and the Kansas City Osteoporosis Study (KCOS, N = 2219). We also cross-validated significant variants in the publicly available body mass index (BMI) summary results (N ~ 700,000). We then performed a series of functional investigations on the identified variants.ResultsFour correlated SNPs at 6p21.1 were identified at the genome-wide significance (GWS, α = 5.0 × 10-8) level in the discovery FHS sample (rs551145, rs524533, rs571770, and rs545970, p = 3.40-9.77 × 10-9), and were successfully replicated in both the WHI-AA and the KCOS samples (one-sided p = 1.61 × 10-3-0.04). They were further cross-validated by the large-scale BMI summary results (p = 7.0-9.8 × 10-3). Cis-eQTL analyses associated these SNPs with the NFKBIE gene expression. Electrophoresis mobility shift assay (EMSA) in mouse C2C12 myoblast cells implied that rs524533 and rs571770 were bound to an unknown transcription factor in an allelic specific manner, while rs551145 and rs545970 did not. Dual-luciferase reporter assay revealed that both rs524533 and rs571770 downregulated luciferase expression by repressing promoter activity. Moreover, the regulation pattern was allelic specific, strengthening the evidence towards their differential regulatory effects.ConclusionsThrough a large-scale GWAS followed by a series of functional investigations, we identified 2 correlated functional variants at 6p21.1 associated with leg lean mass. Our findings not only enhanced our understanding of molecular basis of lean mass development but also provided useful candidate genes for further functional studies.

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Disentangling the genetics of lean mass.

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Disentangling the genetics of lean mass.

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