Disentangling the genetics of lean mass

Research output: Contribution to journalJournal articleResearchpeer-review

David Karasik, M. Carola Zillikens, Yi Hsiang Hsu, Ali Aghdassi, Kristina Akesson, Najaf Amin, Inês Barroso, David A. Bennett, Lars Bertram, Murielle Bochud, Ingrid B. Borecki, Linda Broer, Aron S. Buchman, Liisa Byberg, Harry Campbell, Natalia Campos-Obando, Jane A. Cauley, Peggy M. Cawthon, John C. Chambers, Zhao Chen & 137 others Nam H. Cho, Hyung Jin Choi, Wen Chi Chou, Steven R. Cummings, Lisette C.P.G.M. de Groot, Phillip L. De Jager, Ilja Demuth, Luda Diatchenko, Michael J. Econs, Gudny Eiriksdottir, Anke W. Enneman, Joel Eriksson, Johan G. Eriksson, Karol Estrada, Daniel S. Evans, Mary F. Feitosa, Mao Fu, Christian Gieger, Harald Grallert, Vilmundur Gudnason, Launer J. Lenore, Caroline Hayward, Albert Hofman, Georg Homuth, Kim M. Huffman, Lise B. Husted, Thomas Illig, Erik Ingelsson, Till Ittermann, John Olov Jansson, Toby Johnson, Reiner Biffar, Joanne M. Jordan, Antti Jula, Magnus Karlsson, Kay Tee Khaw, Tuomas O. Kilpeläinen, Norman Klopp, Jacqueline S.L. Kloth, Daniel L. Koller, Jaspal S. Kooner, William E. Kraus, Stephen Kritchevsky, Zoltán Kutalik, Teemu Kuulasmaa, Johanna Kuusisto, Markku Laakso, Jari Lahti, Thomas Lang, Bente L. Langdahl, Markus M. Lerch, Joshua R. Lewis, Christina Lill, Lars Lind, Cecilia Lindgren, Yongmei Liu, Gregory Livshits, Östen Ljunggren, Ruth J.F. Loos, Mattias Lorentzon, Jian'an Luan, Robert N. Luben, Ida Malkin, Fiona E. McGuigan, Carolina Medina-Gomez, Thomas Meitinger, Håkan Melhus, Dan Mellström, Karl Michaëlsson, Braxton D. Mitchell, Andrew P. Morris, Leif Mosekilde, Maria Nethander, Anne B. Newman, Jeffery R. O'Connell, Ben A. Oostra, Eric S. Orwoll, Aarno Palotie, Munro Peacock, Markus Perola, Annette Peters, Richard L. Prince, Bruce M. Psaty, Katri Räikkönen, Stuart H. Ralston, Samuli Ripatti, Fernando Rivadeneira, John A. Robbins, Jerome I. Rotter, Igor Rudan, Veikko Salomaa, Suzanne Satterfield, Sabine Schipf, Chan Soo Shin, Albert V. Smith, Shad B. Smith, Nicole Soranzo, Timothy D. Spector, Alena Stancáková, Kari Stefansson, Elisabeth Steinhagen-Thiessen, Lisette Stolk, Elizabeth A. Streeten, Unnur Styrkarsdottir, Karin M.A. Swart, Patricia Thompson, Cynthia A. Thomson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Emmi Tikkanen, Gregory J. Tranah, André G. Uitterlinden, Cornelia M. van Duijn, Natasja M. van Schoor, Liesbeth Vandenput, Peter Vollenweider, Henry Völzke, Jean Wactawski-Wende, Mark Walker, Nicholas J Wareham, Dawn Waterworth, Michael N. Weedon, H. Erich Wichmann, Elisabeth Widen, Frances M.K. Williams, James F. Wilson, Nicole C. Wright, Laura M. Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Yanhua Zhou, Carrie M. Nielson, Tamara B. Harris, Serkalem Demissie, Douglas P. Kiel, Claes Ohlsson

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.

Original languageEnglish
Book seriesThe American journal of clinical nutrition
Volume109
Issue number2
Pages (from-to)276-287
Number of pages12
ISSN0002-9165
DOIs
Publication statusPublished - 1 Feb 2019

ID: 213714329