Browsing by Author "Evans, Daniel S."

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    Disentangling the genetics of lean mass
    (Oxford University Press, 2019-02-01) Karasik, David; Zillikens, M. Carola; Hsu, Yi-Hsiang; Aghdassi, Ali; Akesson, Kristina; Amin, Najaf; Barroso, Inês; Bennett, David A.; Bertram, Lars; Bochud, Murielle; Borecki, Ingrid B.; Broer, Linda; Buchman, Aron S.; Byberg, Liisa; Campbell, Harry; Campos-Obando, Natalia; Cauley, Jane A.; Cawthon, Peggy M.; Chambers, John C.; Chen, Zhao; Cho, Nam H.; Choi, Hyung Jin; Chou, Wen-Chi; Cummings, Steven R.; De Groot, Lisette C. P. G. M.; De Jager, Phillip L.; Demuth, Ilja; Diatchenko, Luda; Econs, Michael J.; Eiriksdottir, Gudny; Enneman, Anke W.; Eriksson, Joel; Eriksson, Johan G.; Estrada, Karol; Evans, Daniel S.; Feitosa, Mary F.; Fu, Mao; Gieger, Christian; Grallert, Harald; Gudnason, Vilmundur; Lenore, Launer J.; Hayward, Caroline; Hofman, Albert; Homuth, Georg; Huffman, Kim M.; Husted, Lise B.; Illig, Thomas; Ingelsson, Erik; Ittermann, Till; Jansson, John-Olov; Johnson, Toby; Biffar, Reiner; Jordan, Joanne M.; Jula, Antti; Karlsson, Magnus; Khaw, Kay-Tee; Kilpeläinen, Tuomas O.; Klopp, Norman; Kloth, Jacqueline S. L.; Koller, Daniel L.; Kooner, Jaspal S.; Kraus, William E.; Kritchevsky, Stephen; Kutalik, Zoltán; Kuulasmaa, Teemu; Kuusisto, Johanna; Laakso, Markku; Lahti, Jari; Lang, Thomas; Langdahl, Bente L.; Lerch, Markus M.; Lewis, Joshua R.; Lill, Christina; Lind, Lars; Lindgren, Cecilia; Liu, Yongmei; Livshits, Gregory; Ljunggren, Östen; Loos, Ruth J. F.; Lorentzon, Mattias; Luan, Jian'an; Luben, Robert N.; Malkin, Ida; McGuigan, Fiona E.; Medina-Gomez, Carolina; Meitinger, Thomas; Melhus, Håkan; Mellström, Dan; Michaëlsson, Karl; Mitchell, Braxton D.; Morris, Andrew P.; Mosekilde, Leif; Nethander, Maria; Newman, Anne B.; O'Connell, Jeffery R.; Oostra, Ben A.; Orwoll, Eric S.; Palotie, Aarno; Peacock, Munro; Perola, Markus; Peters, Annette; Prince, Richard L.; Psaty, Bruce M.; Räikkönen, Katri; Ralston, Stuart H.; Ripatti, Samuli; Rivadeneira, Fernando; Robbins, John A.; Rotter, Jerome I.; Rudan, Igor; Salomaa, Veikko; Satterfield, Suzanne; Schipf, Sabine; Shin, Chan Soo; Smith, Albert V.; Smith, Shad B.; Soranzo, Nicole; Spector, Timothy D.; Stančáková, Alena; Stefansson, Kari; Steinhagen-Thiessen, Elisabeth; Stolk, Lisette; Streeten, Elizabeth A.; Styrkarsdottir, Unnur; Swart, Karin M. A.; Thompson, Patricia; Thomson, Cynthia A.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Tranah, Gregory J.; Uitterlinden, André G.; Van Duijn, Cornelia M.; Van Schoor, Natasja M.; Vandenput, Liesbeth; Vollenweider, Peter; Völzke, Henry; Wactawski-Wende, Jean; Walker, Mark; Wareham, Nicholas J.; Waterworth, Dawn; Weedon, Michael N.; Wichmann, H-Erich.; Widen, Elisabeth; Williams, Frances M. K.; Wilson, James F.; Wright, Nicole C.; Yerges-Armstrong, Laura M.; Yu, Lei; Zhang, Weihua; Zhao, Jing Hua; Zhou, Yanhua; Nielson, Carrie M.; Harris, Tamara B.; Demissie, Serkalem; Kiel, Douglas P.; Ohlsson, Claes; Medicine, School of Medicine
    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.
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    Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling
    (Elsevier, 2017-11-28) Dole, Neha S.; Mazur, Courtney M.; Acevedo, Claire; Lopez, Justin P.; Monteiro, David A.; Fowler, Tristan W.; Gludovatz, Bernd; Walsh, Flynn; Regan, Jenna N.; Messina, Sara; Evans, Daniel S.; Lang, Thomas F.; Zhang, Bin; Ritchie, Robert O.; Mohammad, Khalid S.; Alliston, Tamara; Medicine, School of Medicine
    Summary Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRIIocy−/−), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.