08678nas a2202593 4500008004100000022001400041245012400055210006900179260001600248300001200264490000700276520126400283653001701547653002601564653004001590653003401630653001101664653001501675653002001690653003001710653003801740653003401778653001301812653001801825653001101843653005001854653005501904653002101959653000901980653004601989653001702035653002002052653003602072653002802108653001702136653001302153100001902166700002602185700002502211700001902236700002002255700002502275700001402300700002302314700001602337700001802353700002202371700001202393700001802405700002102423700002202444700002402466700001802490700001702508700003102525700002002556700001802576700001902594700002502613700002402638700001702662700002502679700002102704700002102725700001702746700001702763700002202780700001902802700002602821700001802847700002102865700002002886700002802906700001902934700002102953700002202974700002502996700002203021700002103043700001703064700002403081700002303105700001703128700002203145700002303167700002003190700001903210700002103229700001603250700002603266700002003292700001903312700002103331700001903352700001903371700002003390700002803410700002103438700001903459700002003478700002003498700002703518700001403545700001303559700002103572700002503593700002403618700001703642700002403659700001803683700002203701700001403723700001803737700002003755700003003775700002003805700002103825700002403846700001803870700002203888700002903910700002303939700001503962700002103977700002103998700001604019700002004035700003104055700002004086700003004106700001904136700002204155700002004177700002404197700002004221700002204241700002004263700001704283700001904300700002704319700002404346700003104370700002004401700002104421700002704442700002604469700001504495700001204510700001804522700002804540700002404568700001604592700002204608700002304630700002604653700002304679700002704702700002004729700001704749700002204766700001904788700002504807700002004832700002304852700002104875700002404896700001904920700002404939700002104963700002004984700002405004700001905028700002405047700001805071700001905089700001805108700002205126700001705148700002305165700002205188700002505210700002705235700002705262700001905289700001905308700002305327700002305350700002005373700001705393700001805410700002405428700002105452700002305473700002505496700002305521700002105544700002505565700002205590700002005612700002205632700002605654700002005680700002005700700002405720700002705744700002505771700002805796700001905824700001905843700002005862700002205882700002105904700002805925700002305953700002505976700002106001700002606022856003606048 2012 eng d a1546-171800aGenome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.0 aGenomewide metaanalysis identifies 56 bone mineral density loci c2012 Apr 15 a491-5010 v443 a
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
10aBone Density10aComputational Biology10aEuropean Continental Ancestry Group10aExtracellular Matrix Proteins10aFemale10aFemur Neck10aFractures, Bone10aGene Expression Profiling10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGlycoproteins10aHumans10aIntercellular Signaling Peptides and Proteins10aLow Density Lipoprotein Receptor-Related Protein-510aLumbar Vertebrae10aMale10aMitochondrial Membrane Transport Proteins10aOsteoporosis10aPhosphoproteins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors10aSpectrin1 aEstrada, Karol1 aStyrkarsdottir, Unnur1 aEvangelou, Evangelos1 aHsu, Yi-Hsiang1 aDuncan, Emma, L1 aNtzani, Evangelia, E1 aOei, Ling1 aAlbagha, Omar, M E1 aAmin, Najaf1 aKemp, John, P1 aKoller, Daniel, L1 aLi, Guo1 aLiu, Ching-Ti1 aMinster, Ryan, L1 aMoayyeri, Alireza1 aVandenput, Liesbeth1 aWillner, Dana1 aXiao, Su-Mei1 aYerges-Armstrong, Laura, M1 aZheng, Hou-Feng1 aAlonso, Nerea1 aEriksson, Joel1 aKammerer, Candace, M1 aKaptoge, Stephen, K1 aLeo, Paul, J1 aThorleifsson, Gudmar1 aWilson, Scott, G1 aWilson, James, F1 aAalto, Ville1 aAlen, Markku1 aAragaki, Aaron, K1 aAspelund, Thor1 aCenter, Jacqueline, R1 aDailiana, Zoe1 aDuggan, David, J1 aGarcia, Melissa1 aGarcía-Giralt, Natalia1 aGiroux, Sylvie1 aHallmans, Göran1 aHocking, Lynne, J1 aHusted, Lise, Bjerre1 aJameson, Karen, A1 aKhusainova, Rita1 aKim, Ghi, Su1 aKooperberg, Charles1 aKoromila, Theodora1 aKruk, Marcin1 aLaaksonen, Marika1 aLaCroix, Andrea, Z1 aLee, Seung, Hun1 aLeung, Ping, C1 aLewis, Joshua, R1 aMasi, Laura1 aMencej-Bedrac, Simona1 aNguyen, Tuan, V1 aNogues, Xavier1 aPatel, Millan, S1 aPrezelj, Janez1 aRose, Lynda, M1 aScollen, Serena1 aSiggeirsdottir, Kristin1 aSmith, Albert, V1 aSvensson, Olle1 aTrompet, Stella1 aTrummer, Olivia1 avan Schoor, Natasja, M1 aWoo, Jean1 aZhu, Kun1 aBalcells, Susana1 aBrandi, Maria, Luisa1 aBuckley, Brendan, M1 aCheng, Sulin1 aChristiansen, Claus1 aCooper, Cyrus1 aDedoussis, George1 aFord, Ian1 aFrost, Morten1 aGoltzman, David1 aGonzález-Macías, Jesús1 aKähönen, Mika1 aKarlsson, Magnus1 aKhusnutdinova, Elza1 aKoh, Jung-Min1 aKollia, Panagoula1 aLangdahl, Bente, Lomholt1 aLeslie, William, D1 aLips, Paul1 aLjunggren, Osten1 aLorenc, Roman, S1 aMarc, Janja1 aMellström, Dan1 aObermayer-Pietsch, Barbara1 aOlmos, José, M1 aPettersson-Kymmer, Ulrika1 aReid, David, M1 aRiancho, José, A1 aRidker, Paul, M1 aRousseau, François1 aSlagboom, Eline1 aTang, Nelson, L S1 aUrreizti, Roser1 aVan Hul, Wim1 aViikari, Jorma1 aZarrabeitia, María, T1 aAulchenko, Yurii, S1 aCastano-Betancourt, Martha1 aGrundberg, Elin1 aHerrera, Lizbeth1 aIngvarsson, Thorvaldur1 aJohannsdottir, Hrefna1 aKwan, Tony1 aLi, Rui1 aLuben, Robert1 aMedina-Gómez, Carolina1 aPalsson, Stefan, Th1 aReppe, Sjur1 aRotter, Jerome, I1 aSigurdsson, Gunnar1 avan Meurs, Joyce, B J1 aVerlaan, Dominique1 aWilliams, Frances, M K1 aWood, Andrew, R1 aZhou, Yanhua1 aGautvik, Kaare, M1 aPastinen, Tomi1 aRaychaudhuri, Soumya1 aCauley, Jane, A1 aChasman, Daniel, I1 aClark, Graeme, R1 aCummings, Steven, R1 aDanoy, Patrick1 aDennison, Elaine, M1 aEastell, Richard1 aEisman, John, A1 aGudnason, Vilmundur1 aHofman, Albert1 aJackson, Rebecca, D1 aJones, Graeme1 aJukema, Wouter1 aKhaw, Kay-Tee1 aLehtimäki, Terho1 aLiu, Yongmei1 aLorentzon, Mattias1 aMcCloskey, Eugene1 aMitchell, Braxton, D1 aNandakumar, Kannabiran1 aNicholson, Geoffrey, C1 aOostra, Ben, A1 aPeacock, Munro1 aPols, Huibert, A P1 aPrince, Richard, L1 aRaitakari, Olli1 aReid, Ian, R1 aRobbins, John1 aSambrook, Philip, N1 aSham, Pak, Chung1 aShuldiner, Alan, R1 aTylavsky, Frances, A1 aDuijn, Cornelia, M1 aWareham, Nick, J1 aCupples, Adrienne, L1 aEcons, Michael, J1 aEvans, David, M1 aHarris, Tamara, B1 aKung, Annie, Wai Chee1 aPsaty, Bruce, M1 aReeve, Jonathan1 aSpector, Timothy, D1 aStreeten, Elizabeth, A1 aZillikens, Carola, M1 aThorsteinsdottir, Unnur1 aOhlsson, Claes1 aKarasik, David1 aRichards, Brent1 aBrown, Matthew, A1 aStefansson, Kari1 aUitterlinden, André, G1 aRalston, Stuart, H1 aIoannidis, John, P A1 aKiel, Douglas, P1 aRivadeneira, Fernando uhttps://chs-nhlbi.org/node/8016