Marouli, EiriniGraff, MariaelisaMedina-Gomez, CarolinaLo, Ken SinWood, Andrew RKjaer, Troels RFine, RebeccaLu, YingchangSchurmann, ClaudiaHighland, Heather MRüeger, SinaThorleifsson, GudmarJustice, Anne ELamparter, DavidStirrups, Kathleen ETurcot, ValérieYoung, Kristin LWinkler, Thomas WEsko, TõnuKaraderi, TugceLocke, Adam EMasca, Nicholas GDNg, Maggie CYMudgal, PoorvaRivas, Manuel AVedantam, SailajaMahajan, AnubhaGuo, XiuqingAbecasis, GoncaloAben, Katja KAdair, Linda SAlam, Dewan SAlbrecht, EvaAllin, Kristine HAllison, MatthewAmouyel, PhilippeAppel, Emil VArveiler, DominiqueAsselbergs, Folkert WAuer, Paul LBalkau, BeverleyBanas, BernhardBang, Lia EBenn, MarianneBergmann, SvenBielak, Lawrence FBlüher, MatthiasBoeing, HeinerBoerwinkle, EricBöger, Carsten ABonnycastle, Lori LBork-Jensen, JetteBots, Michiel LBottinger, Erwin PBowden, Donald WBrandslund, IvanBreen, GeromeBrilliant, Murray HBroer, LindaBurt, Amber AButterworth, Adam SCarey, David JCaulfield, Mark JChambers, John CChasman, DanielChen, Yii-Der IdaChowdhury, RajivChristensen, CramerChu, Audrey YCocca, MassimilianoCollins, Francis SCook, James PCorley, JanieGalbany, Jordi CorominasCox, Amanda JCuellar-Partida, GabrielDanesh, JohnDavies, Gailde Bakker, Paul IWde Borst, Gert J.de Denus, Simonde Groot, Mark CHde Mutsert, RenéeDeary, Ian JDedoussis, GeorgeDemerath, Ellen Wden Hollander, Anneke IDennis, Joe GDi Angelantonio, EmanueleDrenos, FotiosDu, MengmengDunning, Alison MEaston, Douglas FEbeling, TapaniEdwards, Todd LEllinor, PatrickElliott, PaulEvangelou, EvangelosFarmaki, Aliki-EleniFaul, Jessica DFeitosa, Mary FFeng, ShuangFerrannini, EleFerrario, Marco MFerrieres, JeanFlorez, JoseFord, IanFornage, MyriamFranks, PaulFrikke-Schmidt, RuthGalesloot, Tessel EGan, WeiGandin, IlariaGasparini, PaoloGiedraitis, VilmantasGiri, AyushGirotto, GiorgiaGordon, Scott DGordon-Larsen, PennyGorski, MathiasGrarup, NielsGrove, Megan L.Gudnason, VilmundurGustafsson, StefanHansen, TorbenHarris, Kathleen MullanHarris, Tamara BHattersley, Andrew THayward, CarolineHe, LiangHeid, Iris MHeikkilä, KaukoHelgeland, ØyvindHernesniemi, JussiHewitt, Alex WHocking, Lynne JHollensted, MetteHolmen, Oddgeir LHovingh, G. KeesHowson, Joanna MMHoyng, Carel BHuang, PaulHveem, KristianIkram, M. ArfanIngelsson, ErikJackson, Anne UJansson, Jan-HåkanJarvik, Gail PJensen, Gorm BJhun, Min AJia, YuchengJiang, XuejuanJohansson, StefanJørgensen, Marit EJørgensen, TorbenJousilahti, PekkaJukema, J WouterKahali, BratatiKahn, René SKähönen, MikaKamstrup, Pia RKanoni, StavroulaKaprio, JaakkoKaraleftheri, MariaKardia, Sharon LRKarpe, FredrikKee, FrankKeeman, RenskeKiemeney, Lambertus AKitajima, HidetoshiKluivers, Kirsten BKocher, ThomasKomulainen, PirjoKontto, JukkaKooner, Jaspal SKooperberg, CharlesKovacs, PeterKriebel, JenniferKuivaniemi, HelenaKüry, SébastienKuusisto, JohannaLa Bianca, MartinaLaakso, MarkkuLakka, Timo ALange, Ethan MLange, Leslie ALangefeld, Carl DLangenberg, ClaudiaLarson, Eric BLee, I-TeLehtimäki, TerhoLewis, Cora ELi, HuaixingLi, JinLi-Gao, RuifangLin, HonghuangLin, Li-AnLin, XuLind, LarsLindström, JaanaLinneberg, AllanLiu, YehengLiu, YongmeiLophatananon, ArtitayaLuan, Jian'anLubitz, StevenLyytikäinen, Leo-PekkaMackey, David AMadden, Pamela AFManning, AlisaMännistö, SatuMarenne, GaëlleMarten, JonathanMartin, Nicholas GMazul, Angela LMeidtner, KarinaMetspalu, AndresMitchell, PaulMohlke, Karen LMook-Kanamori, Dennis OMorgan, AnnaMorris, Andrew DMorris, Andrew PMüller-Nurasyid, MartinaMunroe, Patricia BNalls, Mike ANauck, MatthiasNelson, Christopher PNeville, MattNielsen, Sune FNikus, KjellNjølstad, Pål RNordestgaard, Børge GNtalla, IoannaO'Connel, Jeffrey ROksa, HeikkiLoohuis, Loes M OldeOphoff, Roel AOwen, Katharine RPackard, Chris JPadmanabhan, SandoshPalmer, Colin NAPasterkamp, GerardPatel, AniruddhPattie, AlisonPedersen, OlufPeissig, Peggy LPeloso, Gina MPennell, Craig EPerola, MarkusPerry, James APerry, John R.B.Person, Thomas NPirie, AilithPolasek, OzrenPosthuma, DanielleRaitakari, Olli TRasheed, AsifRauramaa, RainerReilly, Dermot FReiner, Alex PRenström, FridaRidker, PaulRioux, John DRobertson, NeilRobino, AntoniettaRolandsson, OlovRudan, IgorRuth, Katherine SSaleheen, DanishSalomaa, VeikkoSamani, Nilesh JSandow, KevinSapkota, YadavSattar, NaveedSchmidt, Marjanka KSchreiner, Pamela JSchulze, Matthias BScott, Robert ASegura-Lepe, Marcelo PShah, SvatiSim, XuelingSivapalaratnam, SutheshSmall, Kerrin SSmith, Albert VernonSmith, Jennifer ASoutham, LorraineSpector, Timothy DSpeliotes, Elizabeth KStarr, John MSteinthorsdottir, ValgerdurStringham, Heather MStumvoll, MichaelSurendran, PraveenHart, Leen M ‘tTansey, Katherine ETardif, Jean-ClaudeTaylor, Kent DTeumer, AlexanderThompson, Deborah JThorsteinsdottir, UnnurThuesen, Betina HTönjes, AnkeTromp, GerardTrompet, StellaTsafantakis, EmmanouilTuomilehto, JaakkoTybjaerg-Hansen, AnneTyrer, Jonathan PUher, RudolfUitterlinden, André GUlivi, Sheilavan der Laan, Sander WVan Der Leij, Andries Rvan Duijn, Cornelia Mvan Schoor, Natasja Mvan Setten, JessicaVarbo, AnetteVarga, Tibor VVarma, RohitEdwards, Digna R VelezVermeulen, Sita HVestergaard, HenrikVitart, VeroniqueVogt, Thomas FVozzi, DiegoWalker, MarkWang, FeijieWang, Carol AWang, ShuaiWang, YiqinWareham, Nicholas JWarren, Helen RWessel, JenniferWillems, Sara MWilson, James GWitte, Daniel RWoods, Michael OWu, YingYaghootkar, HaniehYao, JieYao, PangYerges-Armstrong, Laura MYoung, RobinZeggini, EleftheriaZhan, XiaoweiZhang, WeihuaZhao, Jing HuaZhao, WeiZheng, HeZhou, WeiRotter, Jerome IBoehnke, MichaelKathiresan, SekarMcCarthy, Mark IWiller, Cristen JStefansson, KariBorecki, Ingrid BLiu, Dajiang JNorth, Kari EHeard-Costa, Nancy LPers, Tune HLindgren, Cecilia MOxvig, ClausKutalik, ZoltánRivadeneira, FernandoLoos, Ruth JFFrayling, Timothy MHirschhorn, JoelDeloukas, PanosLettre, Guillaume2017-11-212016Marouli, E., M. Graff, C. Medina-Gomez, K. S. Lo, A. R. Wood, T. R. Kjaer, R. S. Fine, et al. 2016. “Rare and low-frequency coding variants alter human adult height.” Nature 542 (7640): 186-190. doi:10.1038/nature21039. http://dx.doi.org/10.1038/nature21039.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375309Summary Height is a highly heritable, classic polygenic trait with ∼700 common associated variants identified so far through genome-wide association studies. Here, we report 83 height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (+1-2 cm/allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate to large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.en-USJournal Article2017-11-2110.1038/nature21039