A common variant of HMGA2 is associated with adult and childhood height in the general population

Michael N. Weedon; Guillaume Lettre; Rachel M. Freathy; Cecilia M. Lindgren; Benjamin F. Voight; John R.B. Perry; Katherine S. Elliott; Rachel Hackett; Candace Guiducci; Beverley Shields; Eleftheria Zeggini; Hana Lango; Valeriya Lyssenko; Nicholas J. Timpson; Noel P. Burtt; Nigel W. Rayner; Richa Saxena; Kristin Ardlie; Jonathan H. Tobias; Andrew R. Ness; Susan M. Ring; Colin N.A. Palmer; Andrew D. Morris; Leena Peltonen; Veikko Salomaa; George Davey Smith; Leif C. Groop; Andrew T. Hattersley; Mark I. McCarthy; Joel N. Hirschhorn; Timothy M. Frayling

doi:10.1038/ng2121

A common variant of HMGA2 is associated with adult and childhood height in the general population

Michael N. Weedon, Guillaume Lettre, Rachel M. Freathy, Cecilia M. Lindgren, Benjamin F. Voight, John R.B. Perry, Katherine S. Elliott, Rachel Hackett, Candace Guiducci, Beverley Shields, Eleftheria Zeggini, Hana Lango, Valeriya Lyssenko, Nicholas J. Timpson, Noel P. Burtt, Nigel W. Rayner, Richa Saxena, Kristin Ardlie, Jonathan H. Tobias, Andrew R. NessSusan M. Ring, Colin N.A. Palmer, Andrew D. Morris, Leena Peltonen, Veikko Salomaa, George Davey Smith, Leif C. Groop, Andrew T. Hattersley, Mark I. McCarthy, Joel N. Hirschhorn, Timothy M. Frayling

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Abstract

Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10 ^-8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10^-11, overall P = 4 × 10^-16, including the genome-wide association data). We also observed the association in children (P = 1 × 10^-6, N = 6,827) and a tall/short case-control study (P = 4 × 10^-6, N = 3,207). We estimate that rs1042725 explains ∼0.3% of population variation in height (∼0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.

Original language	English
Pages (from-to)	1245-1250
Number of pages	6
Journal	Nature Genetics
Volume	39
Issue number	10
DOIs	https://doi.org/10.1038/ng2121
State	Published - Oct 2007
Externally published	Yes

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Weedon, M. N., Lettre, G., Freathy, R. M., Lindgren, C. M., Voight, B. F., Perry, J. R. B., Elliott, K. S., Hackett, R., Guiducci, C., Shields, B., Zeggini, E., Lango, H., Lyssenko, V., Timpson, N. J., Burtt, N. P., Rayner, N. W., Saxena, R., Ardlie, K., Tobias, J. H., ... Frayling, T. M. (2007). A common variant of HMGA2 is associated with adult and childhood height in the general population. Nature Genetics, 39(10), 1245-1250. https://doi.org/10.1038/ng2121

@article{3adb65fbec5749e19bfa3e51785ca280,

title = "A common variant of HMGA2 is associated with adult and childhood height in the general population",

abstract = "Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10 -8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10-11, overall P = 4 × 10-16, including the genome-wide association data). We also observed the association in children (P = 1 × 10-6, N = 6,827) and a tall/short case-control study (P = 4 × 10-6, N = 3,207). We estimate that rs1042725 explains ∼0.3% of population variation in height (∼0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.",

author = "Weedon, {Michael N.} and Guillaume Lettre and Freathy, {Rachel M.} and Lindgren, {Cecilia M.} and Voight, {Benjamin F.} and Perry, {John R.B.} and Elliott, {Katherine S.} and Rachel Hackett and Candace Guiducci and Beverley Shields and Eleftheria Zeggini and Hana Lango and Valeriya Lyssenko and Timpson, {Nicholas J.} and Burtt, {Noel P.} and Rayner, {Nigel W.} and Richa Saxena and Kristin Ardlie and Tobias, {Jonathan H.} and Ness, {Andrew R.} and Ring, {Susan M.} and Palmer, {Colin N.A.} and Morris, {Andrew D.} and Leena Peltonen and Veikko Salomaa and Smith, {George Davey} and Groop, {Leif C.} and Hattersley, {Andrew T.} and McCarthy, {Mark I.} and Hirschhorn, {Joel N.} and Frayling, {Timothy M.}",

note = "Funding Information: For the studies using the Scandinavian, US and Polish samples, the work was supported by a March of Dimes grant (#6-FY04-61) to J.N.H. and by a grant from The Center of Excellence in Complex Disease Genetics of the Academy of Finland (EU Projects GenomEUtwin, QLG2-CT-2002-01254) (L.P.). The FINRISK study was supported by the Sigrid Juselius Foundation. We thank members of our laboratories and of the Altshuler and Daly laboratories for helpful discussion, and we gratefully acknowledge all of the participants in the studies. We also thank J. Butler for excellent technical assistance and M. Kuokkanen for logistical help with the FINRISK97 cohort. The whole-genome genotyping and analysis in the DGI genome scan (see Supplementary Note online for contributors) was supported by Novartis Institutes for BioMedical Research (to D. Altshuler), with additional support from The Richard and Susan Smith Family Foundation/American Diabetes Association Pinnacle Program Project Award (to D. Altshuler, J.N.H. and M.J. Daly). R.S. is supported by a US National Institutes of Health (NIH) Research Service Award. G.L. is supported by a March of Dimes research grant (6-FY04-61). Members of the DGI study group acknowledge support from an NIH/National Heart, Lung, and Blood Institute grant (U01 HG004171), the Burroughs Wellcome Fund and the Doris Duke Charitable Foundation. L.C.G. and members of the Botnia Study were funded by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, the Folkhalsan Research Foundation and Clinical Research Institute HUCH. The Malm{\"o} Study was funded by a Linn{\'e} grant from the Swedish Research Council. L.C.G. is supported principally by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH. Work in Malm{\"o}, Sweden was also funded by a Linn{\'e} grant from the Swedish Research Council. We thank the Botnia and Skara research teams for clinical contributions, and colleagues at Massachusetts General Hospital, Harvard, Broad and Novartis for discussions. Funding Information: For the UK-based studies, collection of the type 2 diabetes cases was supported by Diabetes UK, BDA Research and the UK Medical Research Council (MRC) (Biomedical Collections Strategic Grant G0000649). The UK Type 2 Diabetes Genetics Consortium collection was supported by the Wellcome Trust (Biomedical Collections Grant GR072960). The ALSPAC study was supported by The UK MRC, the Wellcome Trust and the University of Bristol. The Exeter Family Study of Childhood Health was supported by UK National Health Service Research and Development and the Wellcome Trust. We also thank the Exeter University Foundation for funding. The UK GWA genotyping was supported by the Wellcome Trust (076113), and replication genotyping was supported by the Wellcome Trust, Diabetes UK, European Commission (EURODIA LSHG-CT-2004-518153) and the Peninsula Medical School. Personal funding comes from the Wellcome Trust (A.T.H.; Research Leave Fellow; Research Career Development Fellow); UK MRC (J.R.B.P.); Diabetes UK (R.M.F.) and the Throne-Holst Foundation (C.M.L.). M.N.W. is Vandervell Foundation Research Fellow at the Peninsula Medical School. C.M.L. is a University of Oxford Nuffield Department of Medicine Scientific Leader Fellow. C.N.A.P. and A.D.M. are supported by the Scottish executive as part of the Generation Scotland Initiative. We acknowledge",

year = "2007",

month = oct,

doi = "10.1038/ng2121",

language = "English",

volume = "39",

pages = "1245--1250",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "10",

}

Weedon, MN, Lettre, G, Freathy, RM, Lindgren, CM, Voight, BF, Perry, JRB, Elliott, KS, Hackett, R, Guiducci, C, Shields, B, Zeggini, E, Lango, H, Lyssenko, V, Timpson, NJ, Burtt, NP, Rayner, NW, Saxena, R, Ardlie, K, Tobias, JH, Ness, AR, Ring, SM, Palmer, CNA, Morris, AD, Peltonen, L, Salomaa, V, Smith, GD, Groop, LC, Hattersley, AT, McCarthy, MI, Hirschhorn, JN & Frayling, TM 2007, 'A common variant of HMGA2 is associated with adult and childhood height in the general population', Nature Genetics, vol. 39, no. 10, pp. 1245-1250. https://doi.org/10.1038/ng2121

TY - JOUR

T1 - A common variant of HMGA2 is associated with adult and childhood height in the general population

AU - Weedon, Michael N.

AU - Lettre, Guillaume

AU - Freathy, Rachel M.

AU - Lindgren, Cecilia M.

AU - Voight, Benjamin F.

AU - Perry, John R.B.

AU - Elliott, Katherine S.

AU - Hackett, Rachel

AU - Guiducci, Candace

AU - Shields, Beverley

AU - Zeggini, Eleftheria

AU - Lango, Hana

AU - Lyssenko, Valeriya

AU - Timpson, Nicholas J.

AU - Burtt, Noel P.

AU - Rayner, Nigel W.

AU - Saxena, Richa

AU - Ardlie, Kristin

AU - Tobias, Jonathan H.

AU - Ness, Andrew R.

AU - Ring, Susan M.

AU - Palmer, Colin N.A.

AU - Morris, Andrew D.

AU - Peltonen, Leena

AU - Salomaa, Veikko

AU - Smith, George Davey

AU - Groop, Leif C.

AU - Hattersley, Andrew T.

AU - McCarthy, Mark I.

AU - Hirschhorn, Joel N.

AU - Frayling, Timothy M.

N1 - Funding Information: For the studies using the Scandinavian, US and Polish samples, the work was supported by a March of Dimes grant (#6-FY04-61) to J.N.H. and by a grant from The Center of Excellence in Complex Disease Genetics of the Academy of Finland (EU Projects GenomEUtwin, QLG2-CT-2002-01254) (L.P.). The FINRISK study was supported by the Sigrid Juselius Foundation. We thank members of our laboratories and of the Altshuler and Daly laboratories for helpful discussion, and we gratefully acknowledge all of the participants in the studies. We also thank J. Butler for excellent technical assistance and M. Kuokkanen for logistical help with the FINRISK97 cohort. The whole-genome genotyping and analysis in the DGI genome scan (see Supplementary Note online for contributors) was supported by Novartis Institutes for BioMedical Research (to D. Altshuler), with additional support from The Richard and Susan Smith Family Foundation/American Diabetes Association Pinnacle Program Project Award (to D. Altshuler, J.N.H. and M.J. Daly). R.S. is supported by a US National Institutes of Health (NIH) Research Service Award. G.L. is supported by a March of Dimes research grant (6-FY04-61). Members of the DGI study group acknowledge support from an NIH/National Heart, Lung, and Blood Institute grant (U01 HG004171), the Burroughs Wellcome Fund and the Doris Duke Charitable Foundation. L.C.G. and members of the Botnia Study were funded by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, the Folkhalsan Research Foundation and Clinical Research Institute HUCH. The Malmö Study was funded by a Linné grant from the Swedish Research Council. L.C.G. is supported principally by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH. Work in Malmö, Sweden was also funded by a Linné grant from the Swedish Research Council. We thank the Botnia and Skara research teams for clinical contributions, and colleagues at Massachusetts General Hospital, Harvard, Broad and Novartis for discussions. Funding Information: For the UK-based studies, collection of the type 2 diabetes cases was supported by Diabetes UK, BDA Research and the UK Medical Research Council (MRC) (Biomedical Collections Strategic Grant G0000649). The UK Type 2 Diabetes Genetics Consortium collection was supported by the Wellcome Trust (Biomedical Collections Grant GR072960). The ALSPAC study was supported by The UK MRC, the Wellcome Trust and the University of Bristol. The Exeter Family Study of Childhood Health was supported by UK National Health Service Research and Development and the Wellcome Trust. We also thank the Exeter University Foundation for funding. The UK GWA genotyping was supported by the Wellcome Trust (076113), and replication genotyping was supported by the Wellcome Trust, Diabetes UK, European Commission (EURODIA LSHG-CT-2004-518153) and the Peninsula Medical School. Personal funding comes from the Wellcome Trust (A.T.H.; Research Leave Fellow; Research Career Development Fellow); UK MRC (J.R.B.P.); Diabetes UK (R.M.F.) and the Throne-Holst Foundation (C.M.L.). M.N.W. is Vandervell Foundation Research Fellow at the Peninsula Medical School. C.M.L. is a University of Oxford Nuffield Department of Medicine Scientific Leader Fellow. C.N.A.P. and A.D.M. are supported by the Scottish executive as part of the Generation Scotland Initiative. We acknowledge

PY - 2007/10

Y1 - 2007/10

N2 - Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10 -8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10-11, overall P = 4 × 10-16, including the genome-wide association data). We also observed the association in children (P = 1 × 10-6, N = 6,827) and a tall/short case-control study (P = 4 × 10-6, N = 3,207). We estimate that rs1042725 explains ∼0.3% of population variation in height (∼0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.

AB - Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10 -8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10-11, overall P = 4 × 10-16, including the genome-wide association data). We also observed the association in children (P = 1 × 10-6, N = 6,827) and a tall/short case-control study (P = 4 × 10-6, N = 3,207). We estimate that rs1042725 explains ∼0.3% of population variation in height (∼0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.

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U2 - 10.1038/ng2121

DO - 10.1038/ng2121

M3 - Article

C2 - 17767157

AN - SCOPUS:34748830310

SN - 1061-4036

VL - 39

SP - 1245

EP - 1250

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

A common variant of HMGA2 is associated with adult and childhood height in the general population

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