Hundreds of variants clustered in genomic loci and biological pathways affect human height - PubMed (original) (raw)

. 2010 Oct 14;467(7317):832-8.

doi: 10.1038/nature09410. Epub 2010 Sep 29.

Karol Estrada, Guillaume Lettre, Sonja I Berndt, Michael N Weedon, Fernando Rivadeneira, Cristen J Willer, Anne U Jackson, Sailaja Vedantam, Soumya Raychaudhuri, Teresa Ferreira, Andrew R Wood, Robert J Weyant, Ayellet V Segrè, Elizabeth K Speliotes, Eleanor Wheeler, Nicole Soranzo, Ju-Hyun Park, Jian Yang, Daniel Gudbjartsson, Nancy L Heard-Costa, Joshua C Randall, Lu Qi, Albert Vernon Smith, Reedik Mägi, Tomi Pastinen, Liming Liang, Iris M Heid, Jian'an Luan, Gudmar Thorleifsson, Thomas W Winkler, Michael E Goddard, Ken Sin Lo, Cameron Palmer, Tsegaselassie Workalemahu, Yurii S Aulchenko, Asa Johansson, M Carola Zillikens, Mary F Feitosa, Tõnu Esko, Toby Johnson, Shamika Ketkar, Peter Kraft, Massimo Mangino, Inga Prokopenko, Devin Absher, Eva Albrecht, Florian Ernst, Nicole L Glazer, Caroline Hayward, Jouke-Jan Hottenga, Kevin B Jacobs, Joshua W Knowles, Zoltán Kutalik, Keri L Monda, Ozren Polasek, Michael Preuss, Nigel W Rayner, Neil R Robertson, Valgerdur Steinthorsdottir, Jonathan P Tyrer, Benjamin F Voight, Fredrik Wiklund, Jianfeng Xu, Jing Hua Zhao, Dale R Nyholt, Niina Pellikka, Markus Perola, John R B Perry, Ida Surakka, Mari-Liis Tammesoo, Elizabeth L Altmaier, Najaf Amin, Thor Aspelund, Tushar Bhangale, Gabrielle Boucher, Daniel I Chasman, Constance Chen, Lachlan Coin, Matthew N Cooper, Anna L Dixon, Quince Gibson, Elin Grundberg, Ke Hao, M Juhani Junttila, Lee M Kaplan, Johannes Kettunen, Inke R König, Tony Kwan, Robert W Lawrence, Douglas F Levinson, Mattias Lorentzon, Barbara McKnight, Andrew P Morris, Martina Müller, Julius Suh Ngwa, Shaun Purcell, Suzanne Rafelt, Rany M Salem, Erika Salvi, Serena Sanna, Jianxin Shi, Ulla Sovio, John R Thompson, Michael C Turchin, Liesbeth Vandenput, Dominique J Verlaan, Veronique Vitart, Charles C White, Andreas Ziegler, Peter Almgren, Anthony J Balmforth, Harry Campbell, Lorena Citterio, Alessandro De Grandi, Anna Dominiczak, Jubao Duan, Paul Elliott, Roberto Elosua, Johan G Eriksson, Nelson B Freimer, Eco J C Geus, Nicola Glorioso, Shen Haiqing, Anna-Liisa Hartikainen, Aki S Havulinna, Andrew A Hicks, Jennie Hui, Wilmar Igl, Thomas Illig, Antti Jula, Eero Kajantie, Tuomas O Kilpeläinen, Markku Koiranen, Ivana Kolcic, Seppo Koskinen, Peter Kovacs, Jaana Laitinen, Jianjun Liu, Marja-Liisa Lokki, Ana Marusic, Andrea Maschio, Thomas Meitinger, Antonella Mulas, Guillaume Paré, Alex N Parker, John F Peden, Astrid Petersmann, Irene Pichler, Kirsi H Pietiläinen, Anneli Pouta, Martin Ridderstråle, Jerome I Rotter, Jennifer G Sambrook, Alan R Sanders, Carsten Oliver Schmidt, Juha Sinisalo, Jan H Smit, Heather M Stringham, G Bragi Walters, Elisabeth Widen, Sarah H Wild, Gonneke Willemsen, Laura Zagato, Lina Zgaga, Paavo Zitting, Helene Alavere, Martin Farrall, Wendy L McArdle, Mari Nelis, Marjolein J Peters, Samuli Ripatti, Joyce B J van Meurs, Katja K Aben, Kristin G Ardlie, Jacques S Beckmann, John P Beilby, Richard N Bergman, Sven Bergmann, Francis S Collins, Daniele Cusi, Martin den Heijer, Gudny Eiriksdottir, Pablo V Gejman, Alistair S Hall, Anders Hamsten, Heikki V Huikuri, Carlos Iribarren, Mika Kähönen, Jaakko Kaprio, Sekar Kathiresan, Lambertus Kiemeney, Thomas Kocher, Lenore J Launer, Terho Lehtimäki, Olle Melander, Tom H Mosley Jr, Arthur W Musk, Markku S Nieminen, Christopher J O'Donnell, Claes Ohlsson, Ben Oostra, Lyle J Palmer, Olli Raitakari, Paul M Ridker, John D Rioux, Aila Rissanen, Carlo Rivolta, Heribert Schunkert, Alan R Shuldiner, David S Siscovick, Michael Stumvoll, Anke Tönjes, Jaakko Tuomilehto, Gert-Jan van Ommen, Jorma Viikari, Andrew C Heath, Nicholas G Martin, Grant W Montgomery, Michael A Province, Manfred Kayser, Alice M Arnold, Larry D Atwood, Eric Boerwinkle, Stephen J Chanock, Panos Deloukas, Christian Gieger, Henrik Grönberg, Per Hall, Andrew T Hattersley, Christian Hengstenberg, Wolfgang Hoffman, G Mark Lathrop, Veikko Salomaa, Stefan Schreiber, Manuela Uda, Dawn Waterworth, Alan F Wright, Themistocles L Assimes, Inês Barroso, Albert Hofman, Karen L Mohlke, Dorret I Boomsma, Mark J Caulfield, L Adrienne Cupples, Jeanette Erdmann, Caroline S Fox, Vilmundur Gudnason, Ulf Gyllensten, Tamara B Harris, Richard B Hayes, Marjo-Riitta Jarvelin, Vincent Mooser, Patricia B Munroe, Willem H Ouwehand, Brenda W Penninx, Peter P Pramstaller, Thomas Quertermous, Igor Rudan, Nilesh J Samani, Timothy D Spector, Henry Völzke, Hugh Watkins, James F Wilson, Leif C Groop, Talin Haritunians, Frank B Hu, Robert C Kaplan, Andres Metspalu, Kari E North, David Schlessinger, Nicholas J Wareham, David J Hunter, Jeffrey R O'Connell, David P Strachan, H-Erich Wichmann, Ingrid B Borecki, Cornelia M van Duijn, Eric E Schadt, Unnur Thorsteinsdottir, Leena Peltonen, André G Uitterlinden, Peter M Visscher, Nilanjan Chatterjee, Ruth J F Loos, Michael Boehnke, Mark I McCarthy, Erik Ingelsson, Cecilia M Lindgren, Gonçalo R Abecasis, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn

Affiliations

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Hana Lango Allen et al. Nature. 2010.

Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

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Figures

Figure 1

Figure 1. Phenotypic variance explained by common variants

(a) Variance explained is higher when SNPs not reaching genome-wide significance are included in the prediction model. The y-axis represents the proportion of variance explained at different _P_-value thresholds from Stage 1. Results are given for five studies that were not part of Stage 1. *Proportion of variation explained by the 180 SNPs. (b) Cumulative number of susceptibility loci expected to be discovered, including already identified loci and as yet undetected loci. The projections are based on loci that achieved a significance level of P<5×10-8 in the initial scan and the distribution of their effect sizes in Stage 2. The dotted red line corresponds to expected phenotypic variance explained by the 110 loci that reached genome-wide significance in Stage 1, were replicated in Stage 2 and had at least 1% power.

Figure 1

Figure 1. Phenotypic variance explained by common variants

(a) Variance explained is higher when SNPs not reaching genome-wide significance are included in the prediction model. The y-axis represents the proportion of variance explained at different _P_-value thresholds from Stage 1. Results are given for five studies that were not part of Stage 1. *Proportion of variation explained by the 180 SNPs. (b) Cumulative number of susceptibility loci expected to be discovered, including already identified loci and as yet undetected loci. The projections are based on loci that achieved a significance level of P<5×10-8 in the initial scan and the distribution of their effect sizes in Stage 2. The dotted red line corresponds to expected phenotypic variance explained by the 110 loci that reached genome-wide significance in Stage 1, were replicated in Stage 2 and had at least 1% power.

Figure 2

Figure 2. Example of a locus with a secondary signal before (a) and after (b) conditioning

The plot is centered on the conditioned SNP (purple diamond) at the locus. r2 is based on the CEU HapMap II samples. The blue line and right hand Y axis represent CEU HapMap II recombination rates. Created using LocusZoom (

http://csg.sph.umich.edu/locuszoom/

).

Figure 2

Figure 2. Example of a locus with a secondary signal before (a) and after (b) conditioning

The plot is centered on the conditioned SNP (purple diamond) at the locus. r2 is based on the CEU HapMap II samples. The blue line and right hand Y axis represent CEU HapMap II recombination rates. Created using LocusZoom (

http://csg.sph.umich.edu/locuszoom/

).

Figure 3

Figure 3. Loci associated with height contain genes related to each other

(a) 180 height-associated SNPs. The y-axis plots GRAIL _P_-values on a log scale. The histogram corresponds to the distribution of GRAIL _P_-values for 1,000 sets of 180 matched SNPs. The scatter plot represents GRAIL results for the 180 height SNPs (blue dots). The black horizontal line marks the median of the GRAIL _P_-values (_P_=0.14). The top 10 keywords linking the genes were: ‘growth’, ‘kinase’, ‘factor’, ‘transcription’, ‘signaling’, ‘binding’, ‘differentiation’, ‘development’, ‘insulin’, ‘bone’. (b) Graphical representation of the connections between SNPs and corresponding genes for the 42 SNPs with GRAIL P<0.01. Thicker and redder lines imply stronger literature-based connectivity.

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