Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height

Matthew B. Lanktree, Yiran Guo, Muhammed Murtaza, Joseph T. Glessner, Swneke D. Bailey, N. Charlotte Onland-Moret, Guillaume Lettre, Halit Ongen, Ramakrishnan Rajagopalan, Toby Johnson, Haiqing Shen, Christopher P. Nelson, Norman Klopp, Jens Baumert, Sandosh Padmanabhan, Nathan Pankratz, James S. Pankow, Sonia Shah, Kira Taylor, John BarnardBas J. Peters, Cliona M. Maloney, Maximilian T. Lobmeyer, Alice Stanton, M. Hadi Zafarmand, Simon P.R. Romaine, Amar Mehta, Erik P.A. Van Iperen, Yan Gong, Tom S. Price, Erin N. Smith, Cecilia E. Kim, Yun R. Li, Folkert W. Asselbergs, Larry D. Atwood, Kristian M. Bailey, Deepak Bhatt, Florianne Bauer, Elijah R. Behr, Tushar Bhangale, Jolanda M.A. Boer, Bernhard O. Boehm, Jonathan P. Bradfield, Morris Brown, Peter S. Braund, Paul R. Burton, Cara Carty, Hareesh R. Chandrupatla, Wei Chen, John Connell, Chrysoula Dalgeorgou, Anthonius De Boer, Fotios Drenos, Clara C. Elbers, James C. Fang, Caroline S. Fox, Edward C. Frackelton, Barry Fuchs, Clement E. Furlong, Quince Gibson, Christian Gieger, Anuj Goel, Diederik E. Grobbee, Claire Hastie, Philip J. Howard, Guan Hua Huang, W. Craig Johnson, Qing Li, Marcus E. Kleber, Barbara E.K. Klein, Ronald Klein, Charles Kooperberg, Bonnie Ky, Andrea Lacroix, Paul Lanken, Mark Lathrop, Mingyao Li, Vanessa Marshall, Olle Melander, Frank D. Mentch, Nuala J. Meyer, Keri L. Monda, Alexandre Montpetit, Gurunathan Murugesan, Karen Nakayama, Dave Nondahl, Abiodun Onipinla, Suzanne Rafelt, Stephen J. Newhouse, F. George Otieno, Sanjey R. Patel, Mary E. Putt, Santiago Rodriguez, Radwan N. Safa, Douglas B. Sawyer, Pamela J. Schreiner, Claire Simpson, Suthesh Sivapalaratnam, Sathanur R. Srinivasan, Christine Suver, Gary Swergold, Nancy K. Sweitzer, Kelly A. Thomas, Barbara Thorand, Nicholas J. Timpson, Sam Tischfield, Martin Tobin, MacIej Tomaszweski, W. M.Monique Verschuren, Chris Wallace, Bernhard Winkelmann, Haitao Zhang, Dongling Zheng, Li Zhang, Joseph M. Zmuda, Robert Clarke, Anthony J. Balmforth, John Danesh, Ian N. Day, Nicholas J. Schork, Paul I.W. De Bakker, Christian Delles, David Duggan, Aroon D. Hingorani, Joel N. Hirschhorn, Marten H. Hofker, Steve E. Humphries, Mika Kivimaki, Debbie A. Lawlor, Kandice Kottke-Marchant, Jessica L. Mega, Braxton D. Mitchell, David A. Morrow, Jutta Palmen, Susan Redline, Denis C. Shields, Alan R. Shuldiner, Patrick M. Sleiman, George Davey Smith, Martin Farrall, Yalda Jamshidi, David C. Christiani, Juan P. Casas, Alistair S. Hall, Pieter A. Doevendans, Jason D. Christie, Gerald S. Berenson, Sarah S. Murray, Thomas Illig, Gerald W. Dorn, Thomas P. Cappola, Eric Boerwinkle, Peter Sever, Daniel J. Rader, Muredach P. Reilly, Mark Caulfield, Philippa J. Talmud, Eric Topol, James C. Engert, Kai Wang, Anna Dominiczak, Anders Hamsten, Sean P. Curtis, Roy L. Silverstein, Leslie A. Lange, Marc S. Sabatine, Mieke Trip, Danish Saleheen, John F. Peden, Karen J. Cruickshanks, Winfried März, Jeffrey R. O'Connell, Olaf H. Klungel, Cisca Wijmenga, Anke Hilse Maitland-Van Der Zee, Eric E. Schadt, Julie A. Johnson, Gail P. Jarvik, George J. Papanicolaou, Struan F.A. Grant, Patricia B. Munroe, Kari E. North, Nilesh J. Samani, Wolfgang Koenig, Tom R. Gaunt, Sonia S. Anand, Yvonne T. Van Der Schouw, Nicole Soranzo, Garret A. Fitzgerald, Alex Reiner, Robert A. Hegele, Hakon Hakonarson, Brendan J. Keating

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10-6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10-8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10-11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Original languageEnglish (US)
Pages (from-to)6-18
Number of pages13
JournalAmerican Journal of Human Genetics
Volume88
Issue number1
DOIs
StatePublished - Jan 7 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Lanktree, M. B., Guo, Y., Murtaza, M., Glessner, J. T., Bailey, S. D., Onland-Moret, N. C., Lettre, G., Ongen, H., Rajagopalan, R., Johnson, T., Shen, H., Nelson, C. P., Klopp, N., Baumert, J., Padmanabhan, S., Pankratz, N., Pankow, J. S., Shah, S., Taylor, K., ... Keating, B. J. (2011). Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height. American Journal of Human Genetics, 88(1), 6-18. https://doi.org/10.1016/j.ajhg.2010.11.007