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 Barnard; Bas 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 Goe; 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 Marshal; Olle Melander; Frank D. Mentch; Nuala J. Meyer; Keri L. Monda; Alexandre Montpetit; Gurunathan Murugesan; Karen Nakayama; Dave Nondah; 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., II 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 Maerz; 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; Hugh Watkins; 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; Meena Kumari; Nicole Soranzo; Garret A. FitzGerald; Alex Reiner; Robert A. Hegele; Hakon Hakonarson; Brendan J. Keating

doi:10.1016/j.ajhg.2010.11.007

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 Goe, 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 Marshal, Olle Melander, Frank D. Mentch, Nuala J. Meyer, Keri L. Monda, Alexandre Montpetit, Gurunathan Murugesan, Karen Nakayama, Dave Nondah, 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., II 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 Maerz, 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, Hugh Watkins, 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, Meena Kumari, Nicole Soranzo, Garret A. FitzGerald, Alex Reiner, Robert A. Hegele, Hakon Hakonarson, Brendan J. Keating

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Pages (from-to)	41443
Journal	American Journal of Human Genetics
Volume	88
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2010.11.007
Publication status	Published - 2011

Subject classification (UKÄ)

Medical Genetics

Access to Document

10.1016/j.ajhg.2010.11.007

Cite this

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), 41443. https://doi.org/10.1016/j.ajhg.2010.11.007

@article{7c5f9559080249c5a37556bfa44523f4,

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

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 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.",

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

year = "2011",

doi = "10.1016/j.ajhg.2010.11.007",

language = "English",

volume = "88",

pages = "41443",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

Lanktree, MB, Guo, Y, Murtaza, M, Glessner, JT, Bailey, SD, Onland-Moret, NC, Lettre, G, Ongen, H, Rajagopalan, R, Johnson, T, Shen, H, Nelson, CP, Klopp, N, Baumert, J, Padmanabhan, S, Pankratz, N, Pankow, JS, Shah, S, Taylor, K, Barnard, J, Peters, BJ, Maloney, CM, Lobmeyer, MT, Stanton, A, Zafarmand, MH, Romaine, SPR, Mehta, A, van Iperen, EPA, Gong, Y, Price, TS, Smith, EN, Kim, CE, Li, YR, Asselbergs, FW, Atwood, LD, Bailey, KM, Bhatt, D, Bauer, F, Behr, ER, Bhangale, T, Boer, JMA, Boehm, BO, Bradfield, JP, Brown, M, Braund, PS, Burton, PR, Carty, C, Chandrupatla, HR, Chen, W, Connell, J, Dalgeorgou, C, de Boer, A, Drenos, F, Elbers, CC, Fang, JC, Fox, CS, Frackelton, EC, Fuchs, B, Furlong, CE, Gibson, Q, Gieger, C, Goe, A, Grobbee, DE, Hastie, C, Howard, PJ, Huang, G-H, Johnson, WC, Li, Q, Kleber, ME, Klein, BEK, Klein, R, Kooperberg, C, Ky, B, LaCroix, A, Lanken, P, Lathrop, M, Li, M, Marshal, V, Melander, O, Mentch, FD, Meyer, NJ, Monda, KL, Montpetit, A, Murugesan, G, Nakayama, K, Nondah, D, Onipinla, A, Rafelt, S, Newhouse, SJ, Otieno, FG, Patel, SR, Putt, ME, Rodriguez, S, Safa, RN, Sawyer, DB, Schreiner, PJ, Simpson, C, Sivapalaratnam, S, Srinivasan, SR, Suver, C, Swergold, G, Sweitzer, NK, Thomas, KA, Thorand, B, Timpson, NJ, Tischfield, S, Tobin, M, Tomaszweski, M, Verschuren, WMM, Wallace, C, Winkelmann, B, Zhang, H, Zheng, D, Zhang, L, Zmuda, JM, Clarke, R, Balmforth, AJ, Danesh, J, Day, IN, Schork, NJ, de Bakker, PIW, Delles, C, Duggan, D, Hingorani, AD, Hirschhorn, JN, Hofker, MH, Humphries, SE, Kivimaki, M, Lawlor, DA, Kottke-Marchant, K, Mega, JL, Mitchell, BD, Morrow, DA, Palmen, J, Redline, S, Shields, DC, Shuldiner, AR, Sleiman, PM, Smith, GD, Farrall, M, Jamshidi, Y, Christiani, DC, Casas, JP, Hall, AS, Doevendans, PA, Christie, JD, Berenson, GS, Murray, SS, Illig, T, Dorn, GWII, Cappola, TP, Boerwinkle, E, Sever, P, Rader, DJ, Reilly, MP, Caulfield, M, Talmud, PJ, Topol, E, Engert, JC, Wang, K, Dominiczak, A, Hamsten, A, Curtis, SP, Silverstein, RL, Lange, LA, Sabatine, MS, Trip, M, Saleheen, D, Peden, JF, Cruickshanks, KJ, Maerz, W, O'Connell, JR, Klungel, OH, Wijmenga, C, Maitland-van der Zee, AH, Schadt, EE, Johnson, JA, Jarvik, GP, Papanicolaou, GJ, Watkins, H, Grant, SFA, Munroe, PB, North, KE, Samani, NJ, Koenig, W, Gaunt, TR, Anand, SS, van der Schouw, YT, Kumari, M, Soranzo, N, FitzGerald, GA, Reiner, A, Hegele, RA, Hakonarson, H & Keating, BJ 2011, 'Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height', American Journal of Human Genetics, vol. 88, no. 1, pp. 41443. https://doi.org/10.1016/j.ajhg.2010.11.007

TY - JOUR

T1 - Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

AU - Lanktree, Matthew B.

AU - Guo, Yiran

AU - Murtaza, Muhammed

AU - Glessner, Joseph T.

AU - Bailey, Swneke D.

AU - Onland-Moret, N. Charlotte

AU - Lettre, Guillaume

AU - Ongen, Halit

AU - Rajagopalan, Ramakrishnan

AU - Johnson, Toby

AU - Shen, Haiqing

AU - Nelson, Christopher P.

AU - Klopp, Norman

AU - Baumert, Jens

AU - Padmanabhan, Sandosh

AU - Pankratz, Nathan

AU - Pankow, James S.

AU - Shah, Sonia

AU - Taylor, Kira

AU - Barnard, John

AU - Peters, Bas J.

AU - Maloney, Cliona M.

AU - Lobmeyer, Maximilian T.

AU - Stanton, Alice

AU - Zafarmand, M. Hadi

AU - Romaine, Simon P. R.

AU - Mehta, Amar

AU - van Iperen, Erik P. A.

AU - Gong, Yan

AU - Price, Tom S.

AU - Smith, Erin N.

AU - Kim, Cecilia E.

AU - Li, Yun R.

AU - Asselbergs, Folkert W.

AU - Atwood, Larry D.

AU - Bailey, Kristian M.

AU - Bhatt, Deepak

AU - Bauer, Florianne

AU - Behr, Elijah R.

AU - Bhangale, Tushar

AU - Boer, Jolanda M. A.

AU - Boehm, Bernhard O.

AU - Bradfield, Jonathan P.

AU - Brown, Morris

AU - Braund, Peter S.

AU - Burton, Paul R.

AU - Carty, Cara

AU - Chandrupatla, Hareesh R.

AU - Chen, Wei

AU - Connell, John

AU - Dalgeorgou, Chrysoula

AU - de Boer, Anthonius

AU - Drenos, Fotios

AU - Elbers, Clara C.

AU - Fang, James C.

AU - Fox, Caroline S.

AU - Frackelton, Edward C.

AU - Fuchs, Barry

AU - Furlong, Clement E.

AU - Gibson, Quince

AU - Gieger, Christian

AU - Goe, Anuj

AU - Grobbee, Diederik E.

AU - Hastie, Claire

AU - Howard, Philip J.

AU - Huang, Guan-Hua

AU - Johnson, W. Craig

AU - Li, Qing

AU - Kleber, Marcus E.

AU - Klein, Barbara E. K.

AU - Klein, Ronald

AU - Kooperberg, Charles

AU - Ky, Bonnie

AU - LaCroix, Andrea

AU - Lanken, Paul

AU - Lathrop, Mark

AU - Li, Mingyao

AU - Marshal, Vanessa

AU - Melander, Olle

AU - Mentch, Frank D.

AU - Meyer, Nuala J.

AU - Monda, Keri L.

AU - Montpetit, Alexandre

AU - Murugesan, Gurunathan

AU - Nakayama, Karen

AU - Nondah, Dave

AU - Onipinla, Abiodun

AU - Rafelt, Suzanne

AU - Newhouse, Stephen J.

AU - Otieno, F. George

AU - Patel, Sanjey R.

AU - Putt, Mary E.

AU - Rodriguez, Santiago

AU - Safa, Radwan N.

AU - Sawyer, Douglas B.

AU - Schreiner, Pamela J.

AU - Simpson, Claire

AU - Sivapalaratnam, Suthesh

AU - Srinivasan, Sathanur R.

AU - Suver, Christine

AU - Swergold, Gary

AU - Sweitzer, Nancy K.

AU - Thomas, Kelly A.

AU - Thorand, Barbara

AU - Timpson, Nicholas J.

AU - Tischfield, Sam

AU - Tobin, Martin

AU - Tomaszweski, Maciej

AU - Verschuren, W. M. Monique

AU - Wallace, Chris

AU - Winkelmann, Bernhard

AU - Zhang, Haitao

AU - Zheng, Dongling

AU - Zhang, Li

AU - Zmuda, Joseph M.

AU - Clarke, Robert

AU - Balmforth, Anthony J.

AU - Danesh, John

AU - Day, Ian N.

AU - Schork, Nicholas J.

AU - de Bakker, Paul I. W.

AU - Delles, Christian

AU - Duggan, David

AU - Hingorani, Aroon D.

AU - Hirschhorn, Joel N.

AU - Hofker, Marten H.

AU - Humphries, Steve E.

AU - Kivimaki, Mika

AU - Lawlor, Debbie A.

AU - Kottke-Marchant, Kandice

AU - Mega, Jessica L.

AU - Mitchell, Braxton D.

AU - Morrow, David A.

AU - Palmen, Jutta

AU - Redline, Susan

AU - Shields, Denis C.

AU - Shuldiner, Alan R.

AU - Sleiman, Patrick M.

AU - Smith, George Davey

AU - Farrall, Martin

AU - Jamshidi, Yalda

AU - Christiani, David C.

AU - Casas, Juan P.

AU - Hall, Alistair S.

AU - Doevendans, Pieter A.

AU - Christie, Jason D.

AU - Berenson, Gerald S.

AU - Murray, Sarah S.

AU - Illig, Thomas

AU - Dorn, Gerald W., II

AU - Cappola, Thomas P.

AU - Boerwinkle, Eric

AU - Sever, Peter

AU - Rader, Daniel J.

AU - Reilly, Muredach P.

AU - Caulfield, Mark

AU - Talmud, Philippa J.

AU - Topol, Eric

AU - Engert, James C.

AU - Wang, Kai

AU - Dominiczak, Anna

AU - Hamsten, Anders

AU - Curtis, Sean P.

AU - Silverstein, Roy L.

AU - Lange, Leslie A.

AU - Sabatine, Marc S.

AU - Trip, Mieke

AU - Saleheen, Danish

AU - Peden, John F.

AU - Cruickshanks, Karen J.

AU - Maerz, Winfried

AU - O'Connell, Jeffrey R.

AU - Klungel, Olaf H.

AU - Wijmenga, Cisca

AU - Maitland-van der Zee, Anke Hilse

AU - Schadt, Eric E.

AU - Johnson, Julie A.

AU - Jarvik, Gail P.

AU - Papanicolaou, George J.

AU - Watkins, Hugh

AU - Grant, Struan F. A.

AU - Munroe, Patricia B.

AU - North, Kari E.

AU - Samani, Nilesh J.

AU - Koenig, Wolfgang

AU - Gaunt, Tom R.

AU - Anand, Sonia S.

AU - van der Schouw, Yvonne T.

AU - Kumari, Meena

AU - Soranzo, Nicole

AU - FitzGerald, Garret A.

AU - Reiner, Alex

AU - Hegele, Robert A.

AU - Hakonarson, Hakon

AU - Keating, Brendan J.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2010.11.007

DO - 10.1016/j.ajhg.2010.11.007

M3 - Article

SN - 0002-9297

VL - 88

SP - 41443

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

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

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