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
Am. J. Clin. Nutr. 109 (2) 276-287 [2019-02-01; online 2019-02-06]
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. To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. 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). 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. 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.