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; John Connell; George Davey Smith; Whitehall II Study, WHII 50K Grp, PROCARDIS

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, John Connell, George Davey Smith, Whitehall II Study, WHII 50K Grp, PROCARDIS

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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)	6-18
Number of pages	13
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 - 7 Jan 2011

Keywords

GENOME-WIDE ASSOCIATION
BIOLOGICAL PATHWAYS
ADULT HEIGHT
LOCI
POPULATION
INTERLEUKIN-11
IDENTIFICATION
HERITABILITY
TRAITS
MICE

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10.1016/j.ajhg.2010.11.007

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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., ... Whitehall II Study, WHII 50K Grp, PROCARDIS (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

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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 = "GENOME-WIDE ASSOCIATION, BIOLOGICAL PATHWAYS, ADULT HEIGHT, LOCI, POPULATION, INTERLEUKIN-11, IDENTIFICATION, HERITABILITY, TRAITS, MICE",

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 John Connell and Smith, {George Davey} and {Whitehall II Study, WHII 50K Grp, PROCARDIS}",

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

language = "English",

volume = "88",

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journal = "American Journal of Human Genetics",

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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, 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, Connell, J, Smith, GD & Whitehall II Study, WHII 50K Grp, PROCARDIS 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. 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 - Connell, John

AU - Smith, George Davey

AU - Whitehall II Study, WHII 50K Grp, PROCARDIS

PY - 2011/1/7

Y1 - 2011/1/7

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 - GENOME-WIDE ASSOCIATION

KW - BIOLOGICAL PATHWAYS

KW - ADULT HEIGHT

KW - LOCI

KW - POPULATION

KW - INTERLEUKIN-11

KW - IDENTIFICATION

KW - HERITABILITY

KW - TRAITS

KW - MICE

U2 - 10.1016/j.ajhg.2010.11.007

DO - 10.1016/j.ajhg.2010.11.007

M3 - Article

C2 - 21194676

SN - 0002-9297

VL - 88

SP - 6

EP - 18

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

Abstract

Keywords

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