Disentangling the genetics of lean mass

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; 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

doi:10.1093/ajcn/nqy272

Disentangling the genetics of lean mass

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 ChenNam 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

14 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Clinical Nutrition
Volume	109
Issue number	2
Pages (from-to)	276-287
Number of pages	12
ISSN	0002-9165
DOIs	https://doi.org/10.1093/ajcn/nqy272
Publication status	Published - 2019

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Karasik, D., Zillikens, M. C., Hsu, Y. H., Aghdassi, A., Akesson, K., Amin, N., Barroso, I., Bennett, D. A., Bertram, L., Bochud, M., Borecki, I. B., Broer, L., Buchman, A. S., Byberg, L., Campbell, H., Campos-Obando, N., Cauley, J. A., Cawthon, P. M., Chambers, J. C., ... Ohlsson, C. (2019). Disentangling the genetics of lean mass. American Journal of Clinical Nutrition, 109(2), 276-287. https://doi.org/10.1093/ajcn/nqy272

Karasik, D, Zillikens, MC, Hsu, YH, Aghdassi, A, Akesson, K, Amin, N, Barroso, I, Bennett, DA, Bertram, L, Bochud, M, Borecki, IB, Broer, L, Buchman, AS, Byberg, L, Campbell, H, Campos-Obando, N, Cauley, JA, Cawthon, PM, Chambers, JC, Chen, Z, Cho, NH, Choi, HJ, Chou, WC, Cummings, SR, de Groot, LCPGM, De Jager, PL, Demuth, I, Diatchenko, L, Econs, MJ, Eiriksdottir, G, Enneman, AW, Eriksson, J, Eriksson, JG, Estrada, K, Evans, DS, Feitosa, MF, Fu, M, Gieger, C, Grallert, H, Gudnason, V, Lenore, LJ, Hayward, C, Hofman, A, Homuth, G, Huffman, KM, Husted, LB, Illig, T, Ingelsson, E, Ittermann, T, Jansson, JO, Johnson, T, Biffar, R, Jordan, JM, Jula, A, Karlsson, M, Khaw, KT, Kilpeläinen, TO, Klopp, N, Kloth, JSL, Koller, DL, Kooner, JS, Kraus, WE, Kritchevsky, S, Kutalik, Z, Kuulasmaa, T, Kuusisto, J, Laakso, M, Lahti, J, Lang, T, Langdahl, BL, Lerch, MM, Lewis, JR, Lill, C, Lind, L, Lindgren, C, Liu, Y, Livshits, G, Ljunggren, Ö, Loos, RJF, Lorentzon, M, Luan, J, Luben, RN, Malkin, I, McGuigan, FE, Medina-Gomez, C, Meitinger, T, Melhus, H, Mellström, D, Michaëlsson, K, Mitchell, BD, Morris, AP, Mosekilde, L, Nethander, M, Newman, AB, O'Connell, JR, Oostra, BA, Orwoll, ES, Palotie, A, Peacock, M, Perola, M, Peters, A, Prince, RL, Psaty, BM, Räikkönen, K, Ralston, SH, Ripatti, S, Rivadeneira, F, Robbins, JA, Rotter, JI, Rudan, I, Salomaa, V, Satterfield, S, Schipf, S, Shin, CS, Smith, AV, Smith, SB, Soranzo, N, Spector, TD, Stancáková, A, Stefansson, K, Steinhagen-Thiessen, E, Stolk, L, Streeten, EA, Styrkarsdottir, U, Swart, KMA, Thompson, P, Thomson, CA, Thorleifsson, G, Thorsteinsdottir, U, Tikkanen, E, Tranah, GJ, Uitterlinden, AG, van Duijn, CM, van Schoor, NM, Vandenput, L, Vollenweider, P, Völzke, H, Wactawski-Wende, J, Walker, M, J Wareham, N, Waterworth, D, Weedon, MN, Wichmann, HE, Widen, E, Williams, FMK, Wilson, JF, Wright, NC, Yerges-Armstrong, LM, Yu, L, Zhang, W, Zhao, JH, Zhou, Y, Nielson, CM, Harris, TB, Demissie, S, Kiel, DP & Ohlsson, C 2019, 'Disentangling the genetics of lean mass', American Journal of Clinical Nutrition, vol. 109, no. 2, pp. 276-287. https://doi.org/10.1093/ajcn/nqy272

@article{f2e0b652780b4c7d84013f24092cb6bc,

title = "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.",

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

year = "2019",

doi = "10.1093/ajcn/nqy272",

language = "English",

volume = "109",

pages = "276--287",

journal = "American Journal of Clinical Nutrition",

issn = "0002-9165",

publisher = "American Society for Nutrition",

number = "2",

}

TY - JOUR

T1 - Disentangling the genetics of lean mass

AU - Karasik, David

AU - Zillikens, M. Carola

AU - Hsu, Yi Hsiang

AU - Aghdassi, Ali

AU - Akesson, Kristina

AU - Amin, Najaf

AU - Barroso, Inês

AU - Bennett, David A.

AU - Bertram, Lars

AU - Bochud, Murielle

AU - Borecki, Ingrid B.

AU - Broer, Linda

AU - Buchman, Aron S.

AU - Byberg, Liisa

AU - Campbell, Harry

AU - Campos-Obando, Natalia

AU - Cauley, Jane A.

AU - Cawthon, Peggy M.

AU - Chambers, John C.

AU - Chen, Zhao

AU - Cho, Nam H.

AU - Choi, Hyung Jin

AU - Chou, Wen Chi

AU - Cummings, Steven R.

AU - de Groot, Lisette C.P.G.M.

AU - De Jager, Phillip L.

AU - Demuth, Ilja

AU - Diatchenko, Luda

AU - Econs, Michael J.

AU - Eiriksdottir, Gudny

AU - Enneman, Anke W.

AU - Eriksson, Joel

AU - Eriksson, Johan G.

AU - Estrada, Karol

AU - Evans, Daniel S.

AU - Feitosa, Mary F.

AU - Fu, Mao

AU - Gieger, Christian

AU - Grallert, Harald

AU - Gudnason, Vilmundur

AU - Lenore, Launer J.

AU - Hayward, Caroline

AU - Hofman, Albert

AU - Homuth, Georg

AU - Huffman, Kim M.

AU - Husted, Lise B.

AU - Illig, Thomas

AU - Ingelsson, Erik

AU - Ittermann, Till

AU - Jansson, John Olov

AU - Johnson, Toby

AU - Biffar, Reiner

AU - Jordan, Joanne M.

AU - Jula, Antti

AU - Karlsson, Magnus

AU - Khaw, Kay Tee

AU - Kilpeläinen, Tuomas O.

AU - Klopp, Norman

AU - Kloth, Jacqueline S.L.

AU - Koller, Daniel L.

AU - Kooner, Jaspal S.

AU - Kraus, William E.

AU - Kritchevsky, Stephen

AU - Kutalik, Zoltán

AU - Kuulasmaa, Teemu

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Lahti, Jari

AU - Lang, Thomas

AU - Langdahl, Bente L.

AU - Lerch, Markus M.

AU - Lewis, Joshua R.

AU - Lill, Christina

AU - Lind, Lars

AU - Lindgren, Cecilia

AU - Liu, Yongmei

AU - Livshits, Gregory

AU - Ljunggren, Östen

AU - Loos, Ruth J.F.

AU - Lorentzon, Mattias

AU - Luan, Jian'an

AU - Luben, Robert N.

AU - Malkin, Ida

AU - McGuigan, Fiona E.

AU - Medina-Gomez, Carolina

AU - Meitinger, Thomas

AU - Melhus, Håkan

AU - Mellström, Dan

AU - Michaëlsson, Karl

AU - Mitchell, Braxton D.

AU - Morris, Andrew P.

AU - Mosekilde, Leif

AU - Nethander, Maria

AU - Newman, Anne B.

AU - O'Connell, Jeffery R.

AU - Oostra, Ben A.

AU - Orwoll, Eric S.

AU - Palotie, Aarno

AU - Peacock, Munro

AU - Perola, Markus

AU - Peters, Annette

AU - Prince, Richard L.

AU - Psaty, Bruce M.

AU - Räikkönen, Katri

AU - Ralston, Stuart H.

AU - Ripatti, Samuli

AU - Rivadeneira, Fernando

AU - Robbins, John A.

AU - Rotter, Jerome I.

AU - Rudan, Igor

AU - Salomaa, Veikko

AU - Satterfield, Suzanne

AU - Schipf, Sabine

AU - Shin, Chan Soo

AU - Smith, Albert V.

AU - Smith, Shad B.

AU - Soranzo, Nicole

AU - Spector, Timothy D.

AU - Stancáková, Alena

AU - Stefansson, Kari

AU - Steinhagen-Thiessen, Elisabeth

AU - Stolk, Lisette

AU - Streeten, Elizabeth A.

AU - Styrkarsdottir, Unnur

AU - Swart, Karin M.A.

AU - Thompson, Patricia

AU - Thomson, Cynthia A.

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Tikkanen, Emmi

AU - Tranah, Gregory J.

AU - Uitterlinden, André G.

AU - van Duijn, Cornelia M.

AU - van Schoor, Natasja M.

AU - Vandenput, Liesbeth

AU - Vollenweider, Peter

AU - Völzke, Henry

AU - Wactawski-Wende, Jean

AU - Walker, Mark

AU - J Wareham, Nicholas

AU - Waterworth, Dawn

AU - Weedon, Michael N.

AU - Wichmann, H. Erich

AU - Widen, Elisabeth

AU - Williams, Frances M.K.

AU - Wilson, James F.

AU - Wright, Nicole C.

AU - Yerges-Armstrong, Laura M.

AU - Yu, Lei

AU - Zhang, Weihua

AU - Zhao, Jing Hua

AU - Zhou, Yanhua

AU - Nielson, Carrie M.

AU - Harris, Tamara B.

AU - Demissie, Serkalem

AU - Kiel, Douglas P.

AU - Ohlsson, Claes

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1093/ajcn/nqy272

DO - 10.1093/ajcn/nqy272

M3 - Journal article

C2 - 30721968

AN - SCOPUS:85061513446

SN - 0002-9165

VL - 109

SP - 276

EP - 287

JO - American Journal of Clinical Nutrition

JF - American Journal of Clinical Nutrition

IS - 2

ER -

Disentangling the genetics of lean mass

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