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Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

Lanktree, Matthew B.; Guo, Yiran; Murtaza, Muhammed; Glessner, Joseph T.; Bailey, Swneke D.; Onland-Moret, N. Charlotte; Lettre, Guillaume; Ongen, Halit; Rajagopalan, Ramakrishnan and Johnson, Toby, et al. (2011) In American Journal of Human Genetics 88(1). p.41443-41443
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 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 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... (More)
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 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 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 x 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. (Less)
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American Journal of Human Genetics
volume
88
issue
1
pages
41443 - 41443
publisher
Cell Press
external identifiers
  • wos:000286501500001
  • scopus:78650904237
ISSN
0002-9297
DOI
10.1016/j.ajhg.2010.11.007
language
English
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yes
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7c5f9559-0802-49c5-a375-56bfa44523f4 (old id 1876662)
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2011-04-01 11:11:11
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@article{7c5f9559-0802-49c5-a375-56bfa44523f4,
  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 &lt; 2.4 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p &lt; 5 x 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 &lt; 3 x 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.},
  author       = {Lanktree, Matthew B. and Guo, Yiran and Murtaza, Muhammed and Glessner, Joseph T. and Bailey, Swneke D. and Onland-Moret, N. Charlotte and Lettre, Guillaume and Ongen, Halit and Rajagopalan, Ramakrishnan and Johnson, Toby and Shen, Haiqing and Nelson, Christopher P. and Klopp, Norman and Baumert, Jens and Padmanabhan, Sandosh and Pankratz, Nathan and Pankow, James S. and Shah, Sonia and Taylor, Kira and Barnard, John and Peters, Bas J. and Maloney, Cliona M. and Lobmeyer, Maximilian T. and Stanton, Alice and Zafarmand, M. Hadi and Romaine, Simon P. R. and Mehta, Amar and van Iperen, Erik P. A. and Gong, Yan and Price, Tom S. and Smith, Erin N. and Kim, Cecilia E. and Li, Yun R. and Asselbergs, Folkert W. and Atwood, Larry D. and Bailey, Kristian M. and Bhatt, Deepak and Bauer, Florianne and Behr, Elijah R. and Bhangale, Tushar and Boer, Jolanda M. A. and Boehm, Bernhard O. and Bradfield, Jonathan P. and Brown, Morris and Braund, Peter S. and Burton, Paul R. and Carty, Cara and Chandrupatla, Hareesh R. and Chen, Wei and Connell, John and Dalgeorgou, Chrysoula and de Boer, Anthonius and Drenos, Fotios and Elbers, Clara C. and Fang, James C. and Fox, Caroline S. and Frackelton, Edward C. and Fuchs, Barry and Furlong, Clement E. and Gibson, Quince and Gieger, Christian and Goe, Anuj and Grobbee, Diederik E. and Hastie, Claire and Howard, Philip J. and Huang, Guan-Hua and Johnson, W. Craig and Li, Qing and Kleber, Marcus E. and Klein, Barbara E. K. and Klein, Ronald and Kooperberg, Charles and Ky, Bonnie and LaCroix, Andrea and Lanken, Paul and Lathrop, Mark and Li, Mingyao and Marshal, Vanessa and Melander, Olle and Mentch, Frank D. and Meyer, Nuala J. and Monda, Keri L. and Montpetit, Alexandre and Murugesan, Gurunathan and Nakayama, Karen and Nondah, Dave and Onipinla, Abiodun and Rafelt, Suzanne and Newhouse, Stephen J. and Otieno, F. George and Patel, Sanjey R. and Putt, Mary E. and Rodriguez, Santiago and Safa, Radwan N. and Sawyer, Douglas B. and Schreiner, Pamela J. and Simpson, Claire and Sivapalaratnam, Suthesh and Srinivasan, Sathanur R. and Suver, Christine and Swergold, Gary and Sweitzer, Nancy K. and Thomas, Kelly A. and Thorand, Barbara and Timpson, Nicholas J. and Tischfield, Sam and Tobin, Martin and Tomaszweski, Maciej and Verschuren, W. M. Monique and Wallace, Chris and Winkelmann, Bernhard and Zhang, Haitao and Zheng, Dongling and Zhang, Li and Zmuda, Joseph M. and Clarke, Robert and Balmforth, Anthony J. and Danesh, John and Day, Ian N. and Schork, Nicholas J. and de Bakker, Paul I. W. and Delles, Christian and Duggan, David and Hingorani, Aroon D. and Hirschhorn, Joel N. and Hofker, Marten H. and Humphries, Steve E. and Kivimaki, Mika and Lawlor, Debbie A. and Kottke-Marchant, Kandice and Mega, Jessica L. and Mitchell, Braxton D. and Morrow, David A. and Palmen, Jutta and Redline, Susan and Shields, Denis C. and Shuldiner, Alan R. and Sleiman, Patrick M. and Smith, George Davey and Farrall, Martin and Jamshidi, Yalda and Christiani, David C. and Casas, Juan P. and Hall, Alistair S. and Doevendans, Pieter A. and Christie, Jason D. and Berenson, Gerald S. and Murray, Sarah S. and Illig, Thomas and Dorn, Gerald W., II and Cappola, Thomas P. and Boerwinkle, Eric and Sever, Peter and Rader, Daniel J. and Reilly, Muredach P. and Caulfield, Mark and Talmud, Philippa J. and Topol, Eric and Engert, James C. and Wang, Kai and Dominiczak, Anna and Hamsten, Anders and Curtis, Sean P. and Silverstein, Roy L. and Lange, Leslie A. and Sabatine, Marc S. and Trip, Mieke and Saleheen, Danish and Peden, John F. and Cruickshanks, Karen J. and Maerz, Winfried and O'Connell, Jeffrey R. and Klungel, Olaf H. and Wijmenga, Cisca and Maitland-van der Zee, Anke Hilse and Schadt, Eric E. and Johnson, Julie A. and Jarvik, Gail P. and Papanicolaou, George J. and Watkins, Hugh and Grant, Struan F. A. and Munroe, Patricia B. and North, Kari E. and Samani, Nilesh J. and Koenig, Wolfgang and Gaunt, Tom R. and Anand, Sonia S. and van der Schouw, Yvonne T. and Kumari, Meena and Soranzo, Nicole and FitzGerald, Garret A. and Reiner, Alex and Hegele, Robert A. and Hakonarson, Hakon and Keating, Brendan J.},
  issn         = {0002-9297},
  language     = {eng},
  number       = {1},
  pages        = {41443--41443},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2010.11.007},
  volume       = {88},
  year         = {2011},
}