A saturated map of common genetic variants associated with human height.
Yengo L., Vedantam S., Marouli E., Sidorenko J., Bartell E., Sakaue S., Graff M., Eliasen AU., Jiang Y., Raghavan S., Miao J., Arias JD., Graham SE., Mukamel RE., Spracklen CN., Yin X., Chen S-H., Ferreira T., Highland HH., Ji Y., Karaderi T., Lin K., Lüll K., Malden DE., Medina-Gomez C., Machado M., Moore A., Rüeger S., Sim X., Vrieze S., Ahluwalia TS., Akiyama M., Allison MA., Alvarez M., Andersen MK., Ani A., Appadurai V., Arbeeva L., Bhaskar S., Bielak LF., Bollepalli S., Bonnycastle LL., Bork-Jensen J., Bradfield JP., Bradford Y., Braund PS., Brody JA., Burgdorf KS., Cade BE., Cai H., Cai Q., Campbell A., Cañadas-Garre M., Catamo E., Chai J-F., Chai X., Chang L-C., Chang Y-C., Chen C-H., Chesi A., Choi SH., Chung R-H., Cocca M., Concas MP., Couture C., Cuellar-Partida G., Danning R., Daw EW., Degenhard F., Delgado GE., Delitala A., Demirkan A., Deng X., Devineni P., Dietl A., Dimitriou M., Dimitrov L., Dorajoo R., Ekici AB., Engmann JE., Fairhurst-Hunter Z., Farmaki A-E., Faul JD., Fernandez-Lopez J-C., Forer L., Francescatto M., Freitag-Wolf S., Fuchsberger C., Galesloot TE., Gao Y., Gao Z., Geller F., Giannakopoulou O., Giulianini F., Gjesing AP., Goel A., Gordon SD., Gorski M., Grove J., Guo X., Gustafsson S., Haessler J., Hansen TF., Havulinna AS., Haworth SJ., He J., Heard-Costa N., Hebbar P., Hindy G., Ho Y-LA., Hofer E., Holliday E., Horn K., Hornsby WE., Hottenga J-J., Huang H., Huang J., Huerta-Chagoya A., Huffman JE., Hung Y-J., Huo S., Hwang MY., Iha H., Ikeda DD., Isono M., Jackson AU., Jäger S., Jansen IE., Johansson I., Jonas JB., Jonsson A., Jørgensen T., Kalafati I-P., Kanai M., Kanoni S., Kårhus LL., Kasturiratne A., Katsuya T., Kawaguchi T., Kember RL., Kentistou KA., Kim H-N., Kim YJ., Kleber ME., Knol MJ., Kurbasic A., Lauzon M., Le P., Lea R., Lee J-Y., Leonard HL., Li SA., Li X., Li X., Liang J., Lin H., Lin S-Y., Liu J., Liu X., Lo KS., Long J., Lores-Motta L., Luan J., Lyssenko V., Lyytikäinen L-P., Mahajan A., Mamakou V., Mangino M., Manichaikul A., Marten J., Mattheisen M., Mavarani L., McDaid AF., Meidtner K., Melendez TL., Mercader JM., Milaneschi Y., Miller JE., Millwood IY., Mishra PP., Mitchell RE., Møllehave LT., Morgan A., Mucha S., Munz M., Nakatochi M., Nelson CP., Nethander M., Nho CW., Nielsen AA., Nolte IM., Nongmaithem SS., Noordam R., Ntalla I., Nutile T., Pandit A., Christofidou P., Pärna K., Pauper M., Petersen ERB., Petersen LV., Pitkänen N., Polašek O., Poveda A., Preuss MH., Pyarajan S., Raffield LM., Rakugi H., Ramirez J., Rasheed A., Raven D., Rayner NW., Riveros C., Rohde R., Ruggiero D., Ruotsalainen SE., Ryan KA., Sabater-Lleal M., Saxena R., Scholz M., Sendamarai A., Shen B., Shi J., Shin JH., Sidore C., Sitlani CM., Slieker RC., Smit RAJ., Smith AV., Smith JA., Smyth LJ., Southam L., Steinthorsdottir V., Sun L., Takeuchi F., Tallapragada DSP., Taylor KD., Tayo BO., Tcheandjieu C., Terzikhan N., Tesolin P., Teumer A., Theusch E., Thompson DJ., Thorleifsson G., Timmers PRHJ., Trompet S., Turman C., Vaccargiu S., van der Laan SW., van der Most PJ., van Klinken JB., van Setten J., Verma SS., Verweij N., Veturi Y., Wang CA., Wang C., Wang L., Wang Z., Warren HR., Bin Wei W., Wickremasinghe AR., Wielscher M., Wiggins KL., Winsvold BS., Wong A., Wu Y., Wuttke M., Xia R., Xie T., Yamamoto K., Yang J., Yao J., Young H., Yousri NA., Yu L., Zeng L., Zhang W., Zhang X., Zhao J-H., Zhao W., Zhou W., Zimmermann ME., Zoledziewska M., Adair LS., Adams HHH., Aguilar-Salinas CA., Al-Mulla F., Arnett DK., Asselbergs FW., Åsvold BO., Attia J., Banas B., Bandinelli S., Bennett DA., Bergler T., Bharadwaj D., Biino G., Bisgaard H., Boerwinkle E., Böger CA., Bønnelykke K., Boomsma DI., Børglum AD., Borja JB., Bouchard C., Bowden DW., Brandslund I., Brumpton B., Buring JE., Caulfield MJ., Chambers JC., Chandak GR., Chanock SJ., Chaturvedi N., Chen Y-DI., Chen Z., Cheng C-Y., Christophersen IE., Ciullo M., Cole JW., Collins FS., Cooper RS., Cruz M., Cucca F., Cupples LA., Cutler MJ., Damrauer SM., Dantoft TM., de Borst GJ., de Groot LCPGM., De Jager PL., de Kleijn DPV., Janaka de Silva H., Dedoussis GV., den Hollander AI., Du S., Easton DF., Elders PJM., Eliassen AH., Ellinor PT., Elmståhl S., Erdmann J., Evans MK., Fatkin D., Feenstra B., Feitosa MF., Ferrucci L., Ford I., Fornage M., Franke A., Franks PW., Freedman BI., Gasparini P., Gieger C., Girotto G., Goddard ME., Golightly YM., Gonzalez-Villalpando C., Gordon-Larsen P., Grallert H., Grant SFA., Grarup N., Griffiths L., Gudnason V., Haiman C., Hakonarson H., Hansen T., Hartman CA., Hattersley AT., Hayward C., Heckbert SR., Heng C-K., Hengstenberg C., Hewitt AW., Hishigaki H., Hoyng CB., Huang PL., Huang W., Hunt SC., Hveem K., Hyppönen E., Iacono WG., Ichihara S., Ikram MA., Isasi CR., Jackson RD., Jarvelin M-R., Jin Z-B., Jöckel K-H., Joshi PK., Jousilahti P., Jukema JW., Kähönen M., Kamatani Y., Kang KD., Kaprio J., Kardia SLR., Karpe F., Kato N., Kee F., Kessler T., Khera AV., Khor CC., Kiemeney LALM., Kim B-J., Kim EK., Kim H-L., Kirchhof P., Kivimaki M., Koh W-P., Koistinen HA., Kolovou GD., Kooner JS., Kooperberg C., Köttgen A., Kovacs P., Kraaijeveld A., Kraft P., Krauss RM., Kumari M., Kutalik Z., Laakso M., Lange LA., Langenberg C., Launer LJ., Le Marchand L., Lee H., Lee NR., Lehtimäki T., Li H., Li L., Lieb W., Lin X., Lind L., Linneberg A., Liu C-T., Liu J., Loeffler M., London B., Lubitz SA., Lye SJ., Mackey DA., Mägi R., Magnusson PKE., Marcus GM., Vidal PM., Martin NG., März W., Matsuda F., McGarrah RW., McGue M., McKnight AJ., Medland SE., Mellström D., Metspalu A., Mitchell BD., Mitchell P., Mook-Kanamori DO., Morris AD., Mucci LA., Munroe PB., Nalls MA., Nazarian S., Nelson AE., Neville MJ., Newton-Cheh C., Nielsen CS., Nöthen MM., Ohlsson C., Oldehinkel AJ., Orozco L., Pahkala K., Pajukanta P., Palmer CNA., Parra EJ., Pattaro C., Pedersen O., Pennell CE., Penninx BWJH., Perusse L., Peters A., Peyser PA., Porteous DJ., Posthuma D., Power C., Pramstaller PP., Province MA., Qi Q., Qu J., Rader DJ., Raitakari OT., Ralhan S., Rallidis LS., Rao DC., Redline S., Reilly DF., Reiner AP., Rhee SY., Ridker PM., Rienstra M., Ripatti S., Ritchie MD., Roden DM., Rosendaal FR., Rotter JI., Rudan I., Rutters F., Sabanayagam C., Saleheen D., Salomaa V., Samani NJ., Sanghera DK., Sattar N., Schmidt B., Schmidt H., Schmidt R., Schulze MB., Schunkert H., Scott LJ., Scott RJ., Sever P., Shiroma EJ., Shoemaker MB., Shu X-O., Simonsick EM., Sims M., Singh JR., Singleton AB., Sinner MF., Smith JG., Snieder H., Spector TD., Stampfer MJ., Stark KJ., Strachan DP., 't Hart LM., Tabara Y., Tang H., Tardif J-C., Thanaraj TA., Timpson NJ., Tönjes A., Tremblay A., Tuomi T., Tuomilehto J., Tusié-Luna M-T., Uitterlinden AG., van Dam RM., van der Harst P., Van der Velde N., van Duijn CM., van Schoor NM., Vitart V., Völker U., Vollenweider P., Völzke H., Wacher-Rodarte NH., Walker M., Wang YX., Wareham NJ., Watanabe RM., Watkins H., Weir DR., Werge TM., Widen E., Wilkens LR., Willemsen G., Willett WC., Wilson JF., Wong T-Y., Woo J-T., Wright AF., Wu J-Y., Xu H., Yajnik CS., Yokota M., Yuan J-M., Zeggini E., Zemel BS., Zheng W., Zhu X., Zmuda JM., Zonderman AB., Zwart J-A., 23andMe Research Team None., VA Million Veteran Program None., DiscovEHR (DiscovEHR and MyCode Community Health Initiative) None., eMERGE (Electronic Medical Records and Genomics Network) None., Lifelines Cohort Study None., PRACTICAL Consortium None., Understanding Society Scientific Group None., Chasman DI., Cho YS., Heid IM., McCarthy MI., Ng MCY., O'Donnell CJ., Rivadeneira F., Thorsteinsdottir U., Sun YV., Tai ES., Boehnke M., Deloukas P., Justice AE., Lindgren CM., Loos RJF., Mohlke KL., North KE., Stefansson K., Walters RG., Winkler TW., Young KL., Loh P-R., Yang J., Esko T., Assimes TL., Auton A., Abecasis GR., Willer CJ., Locke AE., Berndt SI., Lettre G., Frayling TM., Okada Y., Wood AR., Visscher PM., Hirschhorn JN.
Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.