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

M.B. Lanktree; Y. Guo; M. Murtaza; J.T. Glessner; S.D. Bailey; N.C. Onland-Moret; G. Lettre; H. Ongen; R. Rajagopalan; T. Johnson; H. Shen; C.P. Nelson; N. Klopp; J. Baumert; S. Padmanabhan; N. Pankratz; J.S. Pankow; S. Shah; K. Taylor; J. Barnard; B.J.M. Peters; C.M. Maloney; M.T. Lobmeyer; A Stanton; M.H. Zafarmand; S.P. Romaine; A. Mehta; E.P. van Iperen; Y Gong; T.S. Price; E.N. Smith; C.E. Kim; Y.R. Li; F.W. Asselbergs; L.D. Atwood; K.M. Bailey; D. Bhatt; F. Bauer; E.R. Behr; T. Bhangale; J.M. Boer; B.O. Boehm; J.P. Bradfield; M. Brown; P.S. Braund; P.R. Burton; C. Carty; H.R. Chandrupatla; W. Chen; J. Connell; C. Dalgeorgou; A. de Boer; F. Drenos; C.C. Elbers; J.C. Fang; C.S. Fox; E.C. Frackelton; B. Fuchs; C.E. Furlong; Q. Gibson; C. Gieger; A. Goel; D.E. Grobbee; C. Hastie; P.J. Howard; G.H. Huang; W.C. Johnson; Q. Li; M.E. Kleber; B.E. Klein; R. Klein; C. Kooperberg; B. Ky; A. Lacroix; P. Lanken; M. Lathrop; M. Li; V. Marshall; O. Melander; F.D. Mentch; N.J. Meyer; K.L. Monda; A. Montpetit; G. Murugesan; K. Nakayama; D. Nondahl; A. Onipinla; S. Rafelt; S.J. Newhouse; F.G. Otieno; S.R. Patel; M.E. Putt; S. Rodriguez; R.N. Safa; D.B. Sawyer; A.H. Maitland-van der Zee; O.H. Klungel; P.I.W. de Bakker; Y.T. van der Schouw

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

M.B. Lanktree, Y. Guo, M. Murtaza, J.T. Glessner, S.D. Bailey, N.C. Onland-Moret, G. Lettre, H. Ongen, R. Rajagopalan, T. Johnson, H. Shen, C.P. Nelson, N. Klopp, J. Baumert, S. Padmanabhan, N. Pankratz, J.S. Pankow, S. Shah, K. Taylor, J. BarnardB.J.M. Peters, C.M. Maloney, M.T. Lobmeyer, A Stanton, M.H. Zafarmand, S.P. Romaine, A. Mehta, E.P. van Iperen, Y Gong, T.S. Price, E.N. Smith, C.E. Kim, Y.R. Li, F.W. Asselbergs, L.D. Atwood, K.M. Bailey, D. Bhatt, F. Bauer, E.R. Behr, T. Bhangale, J.M. Boer, B.O. Boehm, J.P. Bradfield, M. Brown, P.S. Braund, P.R. Burton, C. Carty, H.R. Chandrupatla, W. Chen, J. Connell, C. Dalgeorgou, A. de Boer, F. Drenos, C.C. Elbers, J.C. Fang, C.S. Fox, E.C. Frackelton, B. Fuchs, C.E. Furlong, Q. Gibson, C. Gieger, A. Goel, D.E. Grobbee, C. Hastie, P.J. Howard, G.H. Huang, W.C. Johnson, Q. Li, M.E. Kleber, B.E. Klein, R. Klein, C. Kooperberg, B. Ky, A. Lacroix, P. Lanken, M. Lathrop, M. Li, V. Marshall, O. Melander, F.D. Mentch, N.J. Meyer, K.L. Monda, A. Montpetit, G. Murugesan, K. Nakayama, D. Nondahl, A. Onipinla, S. Rafelt, S.J. Newhouse, F.G. Otieno, S.R. Patel, M.E. Putt, S. Rodriguez, R.N. Safa, D.B. Sawyer, A.H. Maitland-van der Zee, O.H. Klungel, P.I.W. de Bakker, Y.T. van der Schouw

Research output: Contribution to journal › Article › Academic › 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	Undefined/Unknown
Pages (from-to)	6-18
Number of pages	13
Journal	American Journal of Human Genetics
Volume	88
Issue number	1
Publication status	Published - 2011

Keywords

Econometric and Statistical Methods: General
Geneeskunde (GENK)
Farmacie/Biofarmaceutische wetenschappen (FARM)
Epidemiology
Farmacie(FARM)
Geneeskunde(GENK)
Medical sciences
Bescherming en bevordering van de menselijke gezondheid
Biomedische technologie en medicijnen
Ziekenhuisstructuur en organisatie van de gezondheidszorg
Public Health

Access to Document

http://www.ncbi.nlm.nih.gov/pubmed/21194676

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., ... van der Schouw, Y. T. (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. http://www.ncbi.nlm.nih.gov/pubmed/21194676

@article{59506c74ab234400a8fd49c6ac0423d0,

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.",

keywords = "Econometric and Statistical Methods: General, Geneeskunde (GENK), Farmacie/Biofarmaceutische wetenschappen (FARM), Epidemiology, Farmacie(FARM), Geneeskunde(GENK), Medical sciences, Bescherming en bevordering van de menselijke gezondheid, Biomedische technologie en medicijnen, Ziekenhuisstructuur en organisatie van de gezondheidszorg, Public Health",

author = "M.B. Lanktree and Y. Guo and M. Murtaza and J.T. Glessner and S.D. Bailey and N.C. Onland-Moret and G. Lettre and H. Ongen and R. Rajagopalan and T. Johnson and H. Shen and C.P. Nelson and N. Klopp and J. Baumert and S. Padmanabhan and N. Pankratz and J.S. Pankow and S. Shah and K. Taylor and J. Barnard and B.J.M. Peters and C.M. Maloney and M.T. Lobmeyer and A Stanton and M.H. Zafarmand and S.P. Romaine and A. Mehta and {van Iperen}, E.P. and Y Gong and T.S. Price and E.N. Smith and C.E. Kim and Y.R. Li and F.W. Asselbergs and L.D. Atwood and K.M. Bailey and D. Bhatt and F. Bauer and E.R. Behr and T. Bhangale and J.M. Boer and B.O. Boehm and J.P. Bradfield and M. Brown and P.S. Braund and P.R. Burton and C. Carty and H.R. Chandrupatla and W. Chen and J. Connell and C. Dalgeorgou and {de Boer}, A. and F. Drenos and C.C. Elbers and J.C. Fang and C.S. Fox and E.C. Frackelton and B. Fuchs and C.E. Furlong and Q. Gibson and C. Gieger and A. Goel and D.E. Grobbee and C. Hastie and P.J. Howard and G.H. Huang and W.C. Johnson and Q. Li and M.E. Kleber and B.E. Klein and R. Klein and C. Kooperberg and B. Ky and A. Lacroix and P. Lanken and M. Lathrop and M. Li and V. Marshall and O. Melander and F.D. Mentch and N.J. Meyer and K.L. Monda and A. Montpetit and G. Murugesan and K. Nakayama and D. Nondahl and A. Onipinla and S. Rafelt and S.J. Newhouse and F.G. Otieno and S.R. Patel and M.E. Putt and S. Rodriguez and R.N. Safa and D.B. Sawyer and {Maitland-van der Zee}, A.H. and O.H. Klungel and {de Bakker}, P.I.W. and {van der Schouw}, Y.T.",

year = "2011",

language = "Undefined/Unknown",

volume = "88",

pages = "6--18",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

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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, BJM, Maloney, CM, Lobmeyer, MT, Stanton, A, Zafarmand, MH, Romaine, SP, Mehta, A, van Iperen, EP, 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, JM, 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, Goel, A, Grobbee, DE, Hastie, C, Howard, PJ, Huang, GH, Johnson, WC, Li, Q, Kleber, ME, Klein, BE, Klein, R, Kooperberg, C, Ky, B, Lacroix, A, Lanken, P, Lathrop, M, Li, M, Marshall, V, Melander, O, Mentch, FD, Meyer, NJ, Monda, KL, Montpetit, A, Murugesan, G, Nakayama, K, Nondahl, D, Onipinla, A, Rafelt, S, Newhouse, SJ, Otieno, FG, Patel, SR, Putt, ME, Rodriguez, S, Safa, RN, Sawyer, DB, Maitland-van der Zee, AH, Klungel, OH, de Bakker, PIW & van der Schouw, YT 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. 6-18. <http://www.ncbi.nlm.nih.gov/pubmed/21194676>

TY - JOUR

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

AU - Lanktree, M.B.

AU - Guo, Y.

AU - Murtaza, M.

AU - Glessner, J.T.

AU - Bailey, S.D.

AU - Onland-Moret, N.C.

AU - Lettre, G.

AU - Ongen, H.

AU - Rajagopalan, R.

AU - Johnson, T.

AU - Shen, H.

AU - Nelson, C.P.

AU - Klopp, N.

AU - Baumert, J.

AU - Padmanabhan, S.

AU - Pankratz, N.

AU - Pankow, J.S.

AU - Shah, S.

AU - Taylor, K.

AU - Barnard, J.

AU - Peters, B.J.M.

AU - Maloney, C.M.

AU - Lobmeyer, M.T.

AU - Stanton, A

AU - Zafarmand, M.H.

AU - Romaine, S.P.

AU - Mehta, A.

AU - van Iperen, E.P.

AU - Gong, Y

AU - Price, T.S.

AU - Smith, E.N.

AU - Kim, C.E.

AU - Li, Y.R.

AU - Asselbergs, F.W.

AU - Atwood, L.D.

AU - Bailey, K.M.

AU - Bhatt, D.

AU - Bauer, F.

AU - Behr, E.R.

AU - Bhangale, T.

AU - Boer, J.M.

AU - Boehm, B.O.

AU - Bradfield, J.P.

AU - Brown, M.

AU - Braund, P.S.

AU - Burton, P.R.

AU - Carty, C.

AU - Chandrupatla, H.R.

AU - Chen, W.

AU - Connell, J.

AU - Dalgeorgou, C.

AU - de Boer, A.

AU - Drenos, F.

AU - Elbers, C.C.

AU - Fang, J.C.

AU - Fox, C.S.

AU - Frackelton, E.C.

AU - Fuchs, B.

AU - Furlong, C.E.

AU - Gibson, Q.

AU - Gieger, C.

AU - Goel, A.

AU - Grobbee, D.E.

AU - Hastie, C.

AU - Howard, P.J.

AU - Huang, G.H.

AU - Johnson, W.C.

AU - Li, Q.

AU - Kleber, M.E.

AU - Klein, B.E.

AU - Klein, R.

AU - Kooperberg, C.

AU - Ky, B.

AU - Lacroix, A.

AU - Lanken, P.

AU - Lathrop, M.

AU - Li, M.

AU - Marshall, V.

AU - Melander, O.

AU - Mentch, F.D.

AU - Meyer, N.J.

AU - Monda, K.L.

AU - Montpetit, A.

AU - Murugesan, G.

AU - Nakayama, K.

AU - Nondahl, D.

AU - Onipinla, A.

AU - Rafelt, S.

AU - Newhouse, S.J.

AU - Otieno, F.G.

AU - Patel, S.R.

AU - Putt, M.E.

AU - Rodriguez, S.

AU - Safa, R.N.

AU - Sawyer, D.B.

AU - Maitland-van der Zee, A.H.

AU - Klungel, O.H.

AU - de Bakker, P.I.W.

AU - van der Schouw, Y.T.

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.

KW - Econometric and Statistical Methods: General

KW - Geneeskunde (GENK)

KW - Farmacie/Biofarmaceutische wetenschappen (FARM)

KW - Epidemiology

KW - Farmacie(FARM)

KW - Geneeskunde(GENK)

KW - Medical sciences

KW - Bescherming en bevordering van de menselijke gezondheid

KW - Biomedische technologie en medicijnen

KW - Ziekenhuisstructuur en organisatie van de gezondheidszorg

KW - Public Health

M3 - Article

SN - 0002-9297

VL - 88

SP - 6

EP - 18

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -