Abstract
Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and replication sample, we identified three genomic loci at the genome-wide significance level (p < 5.0 × 10–8): 2p23.2 (lead SNP rs4477866, discovery p = 3.47 × 10–8, replication p = 1.03 × 10–4), 16q12.2 (rs1421085, discovery p = 2.04 × 10–9, replication p = 6.47 × 10–14) and 18q21.32 (rs11152213, discovery p = 3.47 × 10–8, replication p = 6.69 × 10–6). Our findings not only provide useful insights into lean mass and bone mass development, but also enhance our understanding of the potential genetic correlation between BMD and LBM.
Data availability
Summary results are available upon request to the corresponding author.
References
Anderson G, Cummings S, Freedman LS, Furberg C, Henderson M, Johnson SR, Kuller L, Manson J, Oberman A, Prentice RL, Rossouw JE (1998) Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials 19:61–109
Arden NK, Spector TD (1997) Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. J Bone Miner Res 12:2076–2081
Berndt SI, Gustafsson S, Magi R, Ganna A, Wheeler E, Feitosa MF, Justice AE, Monda KL, Croteau-Chonka DC, Day FR, Esko T, Fall T, Ferreira T, Gentilini D, Jackson AU, Luan JA, Randall JC, Vedantam S, Willer CJ, Winkler TW, Wood AR, Workalemahu T, Hu YJ, Lee SH, Liang LM, Lin DY, Min JL, Neale BM, Thorleifsson G, Yang J, Albrecht E, Amin N, Bragg-Gresham JL, Cadby G, den Heijer M, Eklund N, Fischer K, Goel A, Hottenga JJ, Huffman JE, Jarick I, Johansson A, Johnson T, Kanoni S, Kleber ME, Konig IR, Kristiansson K, Kutalik Z, Lamina C, Lecoeur C, Li G, Mangino M, McArdle WL, Medina-Gomez C, Muller-Nurasyid M, Ngwa JS, Nolte IM, Lavinia P, Pechlivanis S, Perola M, Peters MJ, Preuss M, Rose LM, Shi JX, Shungin D, Smith AV, Strawbridge RJ, Surakka I, Teumer A, Trip MD, Tyrer J, Van Vliet-Ostaptchouk JV, Vandenput L, Waite LL, Zhao JH, Absher D, Asselbergs FW, Atalay M, Attwood AP, Balmforth AJ, Basart H, Beilby J, Bonnycastle LL, Brambilla P, Bruinenberg M, Campbell H, Chasman DI, Chines PS, Collins FS, Connell JM, Cookson WO, de Faire U, de Vegt F, Dei M, Dimitriou M, Edkins S, Estrada K, Evans DM, Farrall M, Ferrario MM, Ferrieres J, Franke L, Frau F, Gejman PV, Grallert H, Gronberg H, Gudnason V, Hall AS, Hall P, Hartikainen AL, Hayward C, Heard-Costa NL, Heath AC, Hebebrand J, Homuth G, Hu FB, Hunt SE, Hypponen E, Iribarren C, Jacobs KB, Jansson JO, Jula A, Kahonen M, Kathiresan S, Kee F, Khaw KT, Kivimaki M, Koenig W, Kraja AT, Kumari M, Kuulasmaa K, Kuusisto J, Laitinen JH, Lakka TA, Langenberg C, Launer LJ, Lind L, Lindstrom J, Liu JJ, Liuzzi A, Lokki ML, Lorentzon M, Madden PA, Magnusson PK, Manunta P, Marek D, Marz W, Leach IM, McKnight B, Medland SE, Mihailov E, Milani L, Montgomery GW, Mooser V, Muhleisen TW, Munroe PB, Musk AW, Narisu N, Navis G, Nicholson G, Nohr EA, Ong KK, Oostra BA, Palmer CNA, Palotie A, Peden JF, Pedersen N, Peters A, Polasek O, Pouta A, Pramstaller PP, Prokopenko I, Putter C, Radhakrishnan A, Raitakari O, Rendon A, Rivadeneira F, Rudan I, Saaristo TE, Sambrook JG, Sanders AR, Sanna S, Saramies J, Schipf S, Schreiber S, Schunkert H, Shin SY, Signorini S, Sinisalo J, Skrobek B, Soranzo N, Stancakova A, Stark K, Stephens JC, Stirrups K, Stolk RP, Stumvoll M, Swift AJ, Theodoraki EV, Thorand B, Tregouet DA, Tremoli E, Van der Klauw MM, van Meurs JBJ, Vermeulen SH, Viikari J, Virtamo J, Vitart V, Waeber G, Wang ZM, Widen E, Wild SH, Willemsen G, Winkelmann BR, Witteman JCM, Wolffenbuttel BHR, Wong A, Wright AF, Zillikens MC, Amouyel P, Boehm BO, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Cupples LA, Cusi D, Dedoussis GV, Erdmann J, Eriksson JG, Franks PW, Froguel P, Gieger C, Gyllensten U, Hamsten A, Harris TB, Hengstenberg C, Hicks AA, Hingorani A, Hinney A, Hofman A, Hovingh KG, Hveem K, Illig T, Jarvelin MR, Jockel KH, Keinanen-Kiukaanniemi SM, Kiemeney LA, Kuh D, Laakso M, Lehtimaki T, Levinson DF, Martin NG, Metspalu A, Morris AD, Nieminen MS, Njolstad I, Ohlsson C, Oldehinkel AJ, Ouwehand WH, Palmer LJ, Penninx B, Power C, Province MA, Psaty BM, Qi L, Rauramaa R, Ridker PM, Ripatti S, Salomaa V, Samani NJ, Snieder H, Sorensen TIA, Spector TD, Stefansson K, Tonjes A, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Vollenweider P, Wallaschofski H, Wareham NJ, Watkins H, Wichmann HE, Wilson JF, Abecasis GR, Assimes TL, Barroso I, Boehnke M, Borecki IB, Deloukas P, Fox CS, Frayling T, Groop LC, Haritunian T, Heid IM, Hunter D, Kaplan RC, Karpe F, Moffatt MF, Mohlke KL, O'Connell JR, Pawitan Y, Schadt EE, Schlessinger D, Steinthorsdottir V, Strachan DP, Thorsteinsdottir U, van Duijn CM, Visscher PM, Di Blasio AM, Hirschhorn JN, Lindgren CM, Morris AP, Meyre D, Scherag A, McCarthy MI, Speliotes EK, North KE, Loos RJF, Ingelsson E (2013) Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat Genet 45:501–U569
Bogl LH, Latvala A, Kaprio J, Sovijarvi O, Rissanen A, Pietilainen KH (2011) An investigation into the relationship between soft tissue body composition and bone mineral density in a young adult twin sample. J Bone Miner Res 26:79–87
Braun TP, Orwoll B, Zhu X, Levasseur PR, Szumowski M, Nguyen ML, Bouxsein ML, Klein RF, Marks DL (2012) Regulation of lean mass, bone mass, and exercise tolerance by the central melanocortin system. PLoS ONE 7:e42183
Cho YL, Min JK, Roh KM, Kim WK, Han BS, Bae KH, Lee SC, Chung SJ, Kang HJ (2015) Phosphoprotein phosphatase 1CB (PPP1CB), a novel adipogenic activator, promotes 3T3-L1 adipogenesis. Biochem Biophys Res Commun 467:211–217
Cummings SR, Melton LJ (2002) Epidemiology and outcomes of osteoporotic fractures. Lancet 359:1761–1767
Edwards MH, Dennison EM, Sayer AA, Fielding R, Cooper C (2015) Osteoporosis and sarcopenia in older age. Bone 80:126–130
Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, Oei L, Albagha OM, Amin N, Kemp JP, Koller DL, Li G, Liu CT, Minster RL, Moayyeri A, Vandenput L, Willner D, Xiao SM, Yerges-Armstrong LM, Zheng HF, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Thorleifsson G, Wilson SG, Wilson JF, Aalto V, Alen M, Aragaki AK, Aspelund T, Center JR, Dailiana Z, Duggan DJ, Garcia M, Garcia-Giralt N, Giroux S, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ, Lee SH, Leung PC, Lewis JR, Masi L, Mencej-Bedrac S, Nguyen TV, Nogues X, Patel MS, Prezelj J, Rose LM, Scollen S, Siggeirsdottir K, Smith AV, Svensson O, Trompet S, Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Buckley BM, Cheng S, Christiansen C, Cooper C, Dedoussis G, Ford I, Frost M, Goltzman D, Gonzalez-Macias J, Kahonen M, Karlsson M, Khusnutdinova E, Koh JM, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren O, Lorenc RS, Marc J, Mellstrom D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NL, Urreizti R, Van Hul W, Viikari J, Zarrabeitia MT, Aulchenko YS, Castano-Betancourt M, Grundberg E, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina-Gomez C, Palsson ST, Reppe S, Rotter JI, Sigurdsson G, van Meurs JB, Verlaan D, Williams FM, Wood AR, Zhou Y, Gautvik KM, Pastinen T, Raychaudhuri S, Cauley JA, Chasman DI, Clark GR, Cummings SR, Danoy P, Dennison EM, Eastell R, Eisman JA, Gudnason V, Hofman A, Jackson RD, Jones G, Jukema JW, Khaw KT, Lehtimaki T, Liu Y, Lorentzon M, McCloskey E, Mitchell BD, Nandakumar K, Nicholson GC, Oostra BA, Peacock M, Pols HA, Prince RL, Raitakari O, Reid IR, Robbins J, Sambrook PN, Sham PC, Shuldiner AR, Tylavsky FA, van Duijn CM, Wareham NJ, Cupples LA, Econs MJ, Evans DM, Harris TB, Kung AW, Psaty BM, Reeve J, Spector TD, Streeten EA, Zillikens MC, Thorsteinsdottir U, Ohlsson C, Karasik D, Richards JB, Brown MA, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JP, Kiel DP, Rivadeneira F (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44:491–501
Fielding RA, Vellas B, Evans WJ, Bhasin S, Morley JE, Newman AB, Abellan van Kan G, Andrieu S, Bauer J, Breuille D, Cederholm T, Chandler J, De Meynard C, Donini L, Harris T, Kannt A, Keime Guibert F, Onder G, Papanicolaou D, Rolland Y, Rooks D, Sieber C, Souhami E, Verlaan S, Zamboni M (2011) Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc 12:249–256
Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, Ruther U (2009) Inactivation of the Fto gene protects from obesity. Nature 458:894–898
Guo YF, Zhang LS, Liu YJ, Hu HG, Li J, Tian Q, Yu P, Zhang F, Yang TL, Guo Y, Peng XL, Dai M, Chen W, Deng HW (2013) Suggestion of GLYAT gene underlying variation of bone size and body lean mass as revealed by a bivariate genome-wide association study. Hum Genet 132:189–199
Hai R, Pei YF, Shen H, Zhang L, Liu XG, Lin Y, Ran S, Pan F, Tan LJ, Lei SF, Yang TL, Zhang Y, Zhu XZ, Zhao LJ, Deng HW (2012a) Genome-wide association study of copy number variation identified gremlin1 as a candidate gene for lean body mass. J Hum Genet 57:33–37
Hai R, Zhang L, Pei YF, Zhao LJ, Ran S, Han YY, Zhu XZ, Shen H, Tian Q, Deng HW (2012b) Bivariate genome-wide association study suggests that the DARC gene influences lean body mass and age at menarche. Sci China Life Sci 55:516–520
Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE, Zheng J, Gregson CL, Grundberg E, Trajanoska K, Logan JG, Pollard AS, Sparkes PC, Ghirardello EJ, Allen R, Leitch VD, Butterfield NC, Komla-Ebri D, Adoum AT, Curry KF, White JK, Kussy F, Greenlaw KM, Xu CJ, Harvey NC, Cooper C, Adams DJ, Greenwood CMT, Maurano MT, Kaptoge S, Rivadeneira F, Tobias JH, Croucher PI, Ackert-Bicknell CL, Bassett JHD, Williams GR, Richards JB, Evans DM (2017) Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet 49:1468
Liu XG, Tan LJ, Lei SF, Liu YJ, Shen H, Wang L, Yan H, Guo YF, Xiong DH, Chen XD, Pan F, Yang TL, Zhang YP, Guo Y, Tang NL, Zhu XZ, Deng HY, Levy S, Recker RR, Papasian CJ, Deng HW (2009a) Genome-wide association and replication studies identified TRHR as an important gene for lean body mass. Am J Hum Genet 84:418–423
Liu YZ, Pei YF, Liu JF, Yang F, Guo Y, Zhang L, Liu XG, Yan H, Wang L, Zhang YP, Levy S, Recker RR, Deng HW (2009b) Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males. PLoS ONE 4:e6827
Lu Y, Quan C, Chen H, Bo X, Zhang C (2017) 3DSNP: a database for linking human noncoding SNPs to their three-dimensional interacting genes. Nucleic Acids Res 45:D643–D649
Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM (2010) Robust relationship inference in genome-wide association studies. Bioinformatics 26:2867–2873
Medina-Gomez C, Kemp JP, Dimou NL, Kreiner E, Chesi A, Zemel BS, Bonnelykke K, Boer CG, Ahluwalia TS, Bisgaard H, Evangelou E, Heppe DHM, Bonewald LF, Gorski JP, Ghanbari M, Demissie S, Duque G, Maurano MT, Kiel DP, Hsu YH, Ackert-Bicknell C, Reppe S, Gautvik KM, Raastad T, Karasik D, van de Peppel J, Jaddoe VWV, Uitterlinden AG, Tobias JH, Grant SFA, Bagos PG, Evans DM, Rivadeneira F (2017) Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus. Nat Commun 8:121
Medina-Gomez C, Kemp JP, Trajanoska K, Luan J, Chesi A, Ahluwalia TS, Mook-Kanamori DO, Ham A, Hartwig FP, Evans DS, Joro R, Nedeljkovic I, Zheng HF, Zhu K, Atalay M, Liu CT, Nethander M, Broer L, Porleifsson G, Mullin BH, Handelman SK, Nalls MA, Jessen LE, Heppe DHM, Richards JB, Wang C, Chawes B, Schraut KE, Amin N, Wareham N, Karasik D, Van der Velde N, Ikram MA, Zemel BS, Zhou Y, Carlsson CJ, Liu Y, McGuigan FE, Boer CG, Bonnelykke K, Ralston SH, Robbins JA, Walsh JP, Zillikens MC, Langenberg C, Li-Gao R, Williams FMK, Harris TB, Akesson K, Jackson RD, Sigurdsson G, den Heijer M, van der Eerden BCJ, van de Peppel J, Spector TD, Pennell C, Horta BL, Felix JF, Zhao JH, Wilson SG, de Mutsert R, Bisgaard H, Styrkarsdottir U, Jaddoe VW, Orwoll E, Lakka TA, Scott R, Grant SFA, Lorentzon M, van Duijn CM, Wilson JF, Stefansson K, Psaty BM, Kiel DP, Ohlsson C, Ntzani E, van Wijnen AJ, Forgetta V, Ghanbari M, Logan JG, Williams GR, Bassett JHD, Croucher PI, Evangelou E, Uitterlinden AG, Ackert-Bicknell CL, Tobias JH, Evans DM, Rivadeneira F (2018) Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects. Am J Hum Genet 102:88–102
Melton LJ 3rd, Khosla S, Crowson CS, O'Connor MK, O'Fallon WM, Riggs BL (2000) Epidemiology of sarcopenia. J Am Geriatr Soc 48:625–630
Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, Vulpescu NA, Forgetta V, Kleinman A, Mohanty ST, Sergio CM, Quinn J, Nguyen-Yamamoto L, Luco AL, Vijay J, Simon MM, Pramatarova A, Medina-Gomez C, Trajanoska K, Ghirardello EJ, Butterfield NC, Curry KF, Leitch VD, Sparkes PC, Adoum AT, Mannan NS, Komla-Ebri DSK, Pollard AS, Dewhurst HF, Hassall TAD, Beltejar MG, Adams DJ, Vaillancourt SM, Kaptoge S, Baldock P, Cooper C, Reeve J, Ntzani EE, Evangelou E, Ohlsson C, Karasik D, Rivadeneira F, Kiel DP, Tobias JH, Gregson CL, Harvey NC, Grundberg E, Goltzman D, Adams DJ, Lelliott CJ, Hinds DA, Ackert-Bicknell CL, Hsu YH, Maurano MT, Croucher PI, Williams GR, Bassett JHD, Evans DM, Richards JB, Me Research T (2019) An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet 51:258–266
Nguyen TV, Howard GM, Kelly PJ, Eisman JA (1998) Bone mass, lean mass, and fat mass: same genes or same environments? Am J Epidemiol 147:3–16
Park JH, Song YM, Sung J, Lee K, Kim YS, Kim T, Cho SI (2012) The association between fat and lean mass and bone mineral density: the Healthy Twin Study. Bone 50:1006–1011
Pei YF, Hu WZ, Yan MW, Li CW, Liu L, Yang XL, Hai R, Wang XY, Shen H, Tian Q, Deng HW, Zhang L (2018) Joint study of two genome-wide association meta-analyses identified 20p12.1 and 20q13.33 for bone mineral density. Bone 110:378–385
Pei YF, Hu WZ, Yang XL, Wei XT, Feng GJ, Zhang H, Shen H, Tian Q, Deng HW, Zhang L (2019a) Two functional variants at 6p21.1 were associated with lean mass. Skelet Muscle 9:28
Pei YF, Liu L, Liu TL, Yang XL, Zhang H, Wei XT, Feng GJ, Hai R, Ran S, Zhang L (2019b) Joint association analysis identified 18 new loci for bone mineral density. J Bone Miner Res 34:1086–1094
Pei YF, Zhang L, Liu YJ, Li J, Shen H, Liu YZ, Tian Q, He H, Wu SY, Ran S, Han YY, Hai R, Lin Y, Zhu JY, Zhu XZ, Papasian CJ, Deng HW (2014) Meta-analysis of genome-wide association data identifies novel susceptibility loci for obesity. Hum Mol Genet 23:820–830
Printen JA, Brady MJ, Saltiel AR (1997) PTG, a protein phosphatase 1-binding protein with a role in glycogen metabolism. Science 275:1475–1478
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506
Rivadeneira F, Zillikens MC, De Laet CE, Hofman A, Uitterlinden AG, Beck TJ, Pols HAP (2007) Femoral neck BMD is a strong predictor of hip fracture susceptibility in elderly men and women because it detects cortical bone instability: the Rotterdam study. J Bone Mineral Res 22:1781–1790
Rolland Y, Czerwinski S, Abellan Van Kan G, Morley JE, Cesari M, Onder G, Woo J, Baumgartner R, Pillard F, Boirie Y, Chumlea WM, Vellas B (2008) Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives. J Nutr Health Aging 12:433–450
Sirola J, Kroger H (2011) Similarities in acquired factors related to postmenopausal osteoporosis and sarcopenia. J Osteoporos 2011:536735
Sonestedt E, Gullberg B, Ericson U, Wirfalt E, Hedblad B, Orho-Melander M (2011) Association between fat intake, physical activity and mortality depending on genetic variation in FTO. Int J Obes (Lond) 35:1041–1049
Sun L, Tan LJ, Lei SF, Chen XD, Li X, Pan R, Yin F, Liu QW, Yan XF, Papasian CJ, Deng HW (2011) Bivariate genome-wide association analyses of femoral neck bone geometry and appendicular lean mass. PLoS ONE 6:e27325
Tan LJ, Wang ZE, Wu KH, Chen XD, Zhu H, Lu S, Tian Q, Liu XG, Papasian CJ, Deng HW (2015) Bivariate genome-wide association study implicates ATP6V1G1 as a novel pleiotropic locus underlying osteoporosis and age at menarche. J Clin Endocrinol Metab 100:E1457–1466
Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934
Zhang H, Liu CT, Wang X (2010) An association test for multiple traits based on the generalized Kendall's tau. J Am Stat Assoc 105:473–481
Zhang L, Pei YF, Fu X, Lin Y, Wang YP, Deng HW (2014) FISH: fast and accurate diploid genotype imputation via segmental hidden Markov model. Bioinformatics 30:1876–1883
Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, Dahia CL, Park-Min KH, Tobias JH, Kooperberg C, Kleinman A, Styrkarsdottir U, Liu CT, Uggla C, Evans DS, Nielson CM, Walter K, Pettersson-Kymmer U, McCarthy S, Eriksson J, Kwan T, Jhamai M, Trajanoska K, Memari Y, Min J, Huang J, Danecek P, Wilmot B, Li R, Chou WC, Mokry LE, Moayyeri A, Claussnitzer M, Cheng CH, Cheung W, Medina-Gomez C, Ge B, Chen SH, Choi K, Oei L, Fraser J, Kraaij R, Hibbs MA, Gregson CL, Paquette D, Hofman A, Wibom C, Tranah GJ, Marshall M, Gardiner BB, Cremin K, Auer P, Hsu L, Ring S, Tung JY, Thorleifsson G, Enneman AW, van Schoor NM, de Groot LC, van der Velde N, Melin B, Kemp JP, Christiansen C, Sayers A, Zhou Y, Calderari S, van Rooij J, Carlson C, Peters U, Berlivet S, Dostie J, Uitterlinden AG, Williams SR, Farber C, Grinberg D, LaCroix AZ, Haessler J, Chasman DI, Giulianini F, Rose LM, Ridker PM, Eisman JA, Nguyen TV, Center JR, Nogues X, Garcia-Giralt N, Launer LL, Gudnason V, Mellstrom D, Vandenput L, Amin N, van Duijn CM, Karlsson MK, Ljunggren O, Svensson O, Hallmans G, Rousseau F, Giroux S, Bussiere J, Arp PP, Koromani F, Prince RL, Lewis JR, Langdahl BL, Hermann AP, Jensen JE, Kaptoge S, Khaw KT, Reeve J, Formosa MM, Xuereb-Anastasi A, Akesson K, McGuigan FE, Garg G, Olmos JM, Zarrabeitia MT, Riancho JA, Ralston SH, Alonso N, Jiang X, Goltzman D, Pastinen T, Grundberg E, Gauguier D, Orwoll ES, Karasik D, Davey-Smith G, Consortium A, Smith AV, Siggeirsdottir K, Harris TB, Zillikens MC, van Meurs JB, Thorsteinsdottir U, Maurano MT, Timpson NJ, Soranzo N, Durbin R, Wilson SG, Ntzani EE, Brown MA, Stefansson K, Hinds DA, Spector T, Cupples LA, Ohlsson C, Greenwood CM, Consortium UK, Jackson RD, Rowe DW, Loomis CA, Evans DM, Ackert-Bicknell CL, Joyner AL, Duncan EL, Kiel DP, Rivadeneira F, Richards JB (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526:112–117
Zhou X, Stephens M (2014) Efficient multivariate linear mixed model algorithms for genome-wide association studies. Nat Methods 11:407–409
Zhu X, Feng T, Tayo BO, Liang J, Young JH, Franceschini N, Smith JA, Yanek LR, Sun YV, Edwards TL, Chen W, Nalls M, Fox E, Sale M, Bottinger E, Rotimi C, Consortium CB, Liu Y, McKnight B, Liu K, Arnett DK, Chakravati A, Cooper RS, Redline S (2015) Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension. Am J Hum Genet 96:21–36
Zillikens MC, Demissie S, Hsu YH, Yerges-Armstrong LM, Chou WC, Stolk L, Livshits G, Broer L, Johnson T, Koller DL, Kutalik Z, Luan J, Malkin I, Ried JS, Smith AV, Thorleifsson G, Vandenput L, Hua Zhao J, Zhang W, Aghdassi A, Akesson K, Amin N, Baier LJ, Barroso I, Bennett DA, Bertram L, Biffar R, Bochud M, Boehnke M, Borecki IB, Buchman AS, Byberg L, Campbell H, Campos Obanda N, Cauley JA, Cawthon PM, Cederberg H, Chen Z, Cho NH, Jin Choi H, Claussnitzer M, Collins F, Cummings SR, De Jager PL, Demuth I, Dhonukshe-Rutten RAM, Diatchenko L, Eiriksdottir G, Enneman AW, Erdos M, Eriksson JG, Eriksson J, Estrada K, Evans DS, Feitosa MF, Fu M, Garcia M, Gieger C, Girke T, Glazer NL, Grallert H, Grewal J, Han BG, Hanson RL, Hayward C, Hofman A, Hoffman EP, Homuth G, Hsueh WC, Hubal MJ, Hubbard A, Huffman KM, Husted LB, Illig T, Ingelsson E, Ittermann T, Jansson JO, Jordan JM, Jula A, Karlsson M, Khaw KT, Kilpelainen TO, Klopp N, Kloth JSL, Koistinen HA, Kraus WE, Kritchevsky S, Kuulasmaa T, Kuusisto J, Laakso M, Lahti J, Lang T, Langdahl BL, Launer LJ, Lee JY, Lerch MM, Lewis JR, Lind L, Lindgren C, Liu Y, Liu T, Liu Y, Ljunggren O, Lorentzon M, Luben RN, Maixner W, McGuigan FE, Medina-Gomez C, Meitinger T, Melhus H, Mellstrom D, Melov S, Michaelsson K, Mitchell BD, Morris AP, Mosekilde L, Newman A, Nielson CM, O'Connell JR, Oostra BA, Orwoll ES, Palotie A, Parker SCJ, Peacock M, Perola M, Peters A, Polasek O, Prince RL, Raikkonen K, Ralston SH, Ripatti S, Robbins JA, Rotter JI, Rudan I, Salomaa V, Satterfield S, Schadt EE, Schipf S, Scott L, Sehmi J, Shen J, Soo Shin C, Sigurdsson G, Smith S, Soranzo N, Stancakova A, Steinhagen-Thiessen E, Streeten EA, Styrkarsdottir U, Swart KMA, Tan ST, Tarnopolsky MA, Thompson P, Thomson CA, Thorsteinsdottir U, Tikkanen E, Tranah GJ, Tuomilehto J, van Schoor NM, Verma A, Vollenweider P, Volzke H, Wactawski-Wende J, Walker M, Weedon MN, Welch R, Wichmann HE, Widen E, Williams FMK, Wilson JF, Wright NC, Xie W, Yu L, Zhou Y, Chambers JC, Doring A, van Duijn CM, Econs MJ, Gudnason V, Kooner JS, Psaty BM, Spector TD, Stefansson K, Rivadeneira F, Uitterlinden AG, Wareham NJ, Ossowski V, Waterworth D, Loos RJF, Karasik D, Harris TB, Ohlsson C, Kiel DP (2017) Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. Nat Commun 8:80
Acknowledgements
We appreciate all the volunteers who participated in this study. This analysis of the UK Biobank sample was conducted using the UK Biobank resource under application number 41542. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract no. N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the Framingham Whole Body and Regional Dual X-ray Absorptiometry (DXA) dataset was provided by NIH grants R01 AR/AG 41398. The datasets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession phs000342.v14.p10. The WHI program is funded by the National Heart, Lung, and Blood Institute, National 20 Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women’s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278. The datasets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession phs000200.v10.p3.
Funding
This study was partially supported by the support from the national natural science foundation of China (31501026 and 31771417 to YFP, 31571291 to LZ), the Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University (201810285048Z), the NIH (R01 AR069055, U19 AG055373, R01 MH104680, R01 AR059781 and P20 GM109036), the Franklin D. Dickson/Missouri Endowment and the Edward G. Schlieder Endowment, and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu higher education institutions. The numerical calculations in this paper have been done on the supercomputing system of the National Supercomputing Center in Changsha. The funders had no role in study design, data collection and analysis, results interpretation or preparation of the manuscript.
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LZ and YFP designed the study. LZ, YFP, YXZ, SSZ, SR, HS, QT, RH, and HWD collected the data. YFP and LZ analyzed the data. YXZ, SSZ, SR, YL, HZ, and XLY performed the literature search. YXZ, SSZ, SR, YL, HZ, XLY, HWD, YFP, and LZ interpreted the data. YXZ, SSZ, and SR generated the figures. YXZ, SSZ, and SR drafted the early version of the manuscript. LZ, YFP supervised the study. All authors were involved in writing the paper and had final approval of the submitted and published versions.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Zhang, YX., Zhang, SS., Ran, S. et al. Three pleiotropic loci associated with bone mineral density and lean body mass. Mol Genet Genomics 296, 55–65 (2021). https://doi.org/10.1007/s00438-020-01724-3
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DOI: https://doi.org/10.1007/s00438-020-01724-3