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Disentangling the genetics of lean mass

Journal article
Authors D. Karasik
M. C. Zillikens
Y. H. Hsu
A. Aghdassi
K. Akesson
N. Amin
I. Barroso
D. A. Bennett
L. Bertram
M. Bochud
I. B. Borecki
L. Broer
A. S. Buchman
L. Byberg
H. Campbell
N. Campos-Obando
J. A. Cauley
P. M. Cawthon
J. C. Chambers
Z. Chen
N. H. Cho
H. J. Choi
W. C. Chou
S. R. Cummings
Lcpgm de Groot
P. L. De Jager
I. Demuth
L. Diatchenko
M. J. Econs
G. Eiriksdottir
A. W. Enneman
Joel Eriksson
J. G. Eriksson
K. Estrada
D. S. Evans
M. F. Feitosa
M. Fu
C. Gieger
H. Grallert
V. Gudnason
L. J. Lenore
C. Hayward
A. Hofman
G. Homuth
K. M. Huffman
L. B. Husted
T. Illig
E. Ingelsson
T. Ittermann
John-Olov Jansson
T. Johnson
R. Biffar
J. M. Jordan
A. Jula
M. Karlsson
K. T. Khaw
T. O. Kilpelainen
N. Klopp
J. S. L. Kloth
D. L. Koller
J. S. Kooner
W. E. Kraus
S. Kritchevsky
Z. Kutalik
T. Kuulasmaa
J. Kuusisto
M. Laakso
J. Lahti
T. Lang
B. L. Langdahl
M. M. Lerch
J. R. Lewis
C. Lill
L. Lind
C. Lindgren
Y. M. Liu
G. Livshits
O. Ljunggren
R. J. F. Loos
Mattias Lorentzon
J. Luan
R. N. Luben
I. Malkin
F. E. McGuigan
C. Medina-Gomez
T. Meitinger
H. Melhus
Dan Mellström
K. Michaelsson
B. D. Mitchell
A. P. Morris
L. Mosekilde
Maria Nethander
A. B. Newman
J. R. O'Connell
B. A. Oostra
E. S. Orwoll
A. Palotie
M. Peacock
M. Perola
A. Peters
R. L. Prince
B. M. Psaty
K. Raikkonen
S. H. Ralston
S. Ripatti
F. Rivadeneira
J. A. Robbins
J. I. Rotter
I. Rudan
V. Salomaa
S. Satterfield
S. Schipf
C. S. Shin
A. V. Smith
S. B. Smith
N. Soranzo
T. D. Spector
A. Stancakova
K. Stefansson
E. Steinhagen-Thiessen
L. Stolk
E. A. Streeten
U. Styrkarsdottir
K. M. A. Swart
P. Thompson
C. A. Thomson
G. Thorleifsson
U. Thorsteinsdottir
E. Tikkanen
G. J. Tranah
A. G. Uitterlinden
C. M. van Duijn
N. M. van Schoor
L. Vandenput
P. Vollenweider
H. Volzke
J. Wactawski-Wende
M. Walker
N. J. Wareham
D. Waterworth
M. N. Weedon
H. E. Wichmann
E. Widen
F. M. K. Williams
J. F. Wilson
N. C. Wright
L. M. Yerges-Armstrong
L. Yu
W. H. Zhang
J. H. Zhao
Y. H. Zhou
C. M. Nielson
T. B. Harris
S. Demissie
D. P. Kiel
Claes Ohlsson
Published in American Journal of Clinical Nutrition
Volume 109
Issue 2
Pages 276-287
ISSN 0002-9165
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Physiology
Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 276-287
Language en
Keywords body composition, skeletal muscle, body fat, meta-analysis of genome-wide association studies, genome-wide association, skeletal-muscle mass, ld score regression, body-mass, susceptibility loci, metaanalysis, insights, density, Nutrition & Dietetics
Subject categories Nutrition and Dietetics


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, age(2), 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 LMwere 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.

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