Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size

Nicole Soranzo; Fernando Rivadeneira; Usha Chinappen-Horsley; Ida Malkina; J. Brent Richards; Naomi Hammond; Lisette Stolk; Alexandra Nica; Michael Inouye; Albert Hofman; Jonathan Stephens; Eleanor Wheeler; Pascal Arp; Rhian Gwilliam; P. Mila Jhamai; Simon Potter; Amy Chaney; Mohammed J.R. Ghori; Radhi Ravindrarajah; Sergey Ermakov; Karol Estrada; Huibert A.P. Pols; Frances M. Williams; Wendy L. McArdle; Joyce B. Van Meurs; Ruth J.F. Loos; Emmanouil T. Dermitzakis; Kourosh R. Ahmadi; Deborah J. Hart; Willem H. Ouwehand; Nicholas J. Wareham; Inês Barroso; Manjinder S. Sandhu; David P. Strachan; Gregory Livshits; Timothy D. Spector; André G. Uitterlinden; Panos Deloukas

doi:10.1371/journal.pgen.1000445

Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size

Nicole Soranzo, Fernando Rivadeneira, Usha Chinappen-Horsley, Ida Malkina, J. Brent Richards, Naomi Hammond, Lisette Stolk, Alexandra Nica, Michael Inouye, Albert Hofman, Jonathan Stephens, Eleanor Wheeler, Pascal Arp, Rhian Gwilliam, P. Mila Jhamai, Simon Potter, Amy Chaney, Mohammed J.R. Ghori, Radhi Ravindrarajah, Sergey ErmakovKarol Estrada, Huibert A.P. Pols, Frances M. Williams, Wendy L. McArdle, Joyce B. Van Meurs, Ruth J.F. Loos, Emmanouil T. Dermitzakis, Kourosh R. Ahmadi, Deborah J. Hart, Willem H. Ouwehand, Nicholas J. Wareham, Inês Barroso, Manjinder S. Sandhu, David P. Strachan, Gregory Livshits, Timothy D. Spector, André G. Uitterlinden, Panos Deloukas^*

^*Corresponding author for this work

Anatomy and Anthropology

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

221 Scopus citations

Abstract

Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GWsignificant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10^-8 and rs910316 in TMED10, P-value = 1.4×10^-7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10^-7 and rs849141 in JAZF1, P-value = 3.2×10^-11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10^-5 and rs6817306 in LCORL, P-value = 4×10^-4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10^-4 and rs4911494 at UQCC, P-value = 1.9×10^-4), and femur length (including rs710841 at PRKG2, Pvalue = 2.4×10^-5 and rs10946808 at HIST1H1D, P-value = 6.4×10^-6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.

Original language	English
Journal	PLoS Genetics
Volume	5
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1000445
State	Published - Apr 2009

Funding

Funders	Funder number
Medical Research Council	MC_U106188470, G0000934, G0701863, MC_qA137934

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10.1371/journal.pgen.1000445

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Soranzo, N., Rivadeneira, F., Chinappen-Horsley, U., Malkina, I., Richards, J. B., Hammond, N., Stolk, L., Nica, A., Inouye, M., Hofman, A., Stephens, J., Wheeler, E., Arp, P., Gwilliam, R., Jhamai, P. M., Potter, S., Chaney, A., Ghori, M. J. R., Ravindrarajah, R., ... Deloukas, P. (2009). Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size. PLoS Genetics, 5(4). https://doi.org/10.1371/journal.pgen.1000445

@article{d4510f20b4264fc7bcb44026395310d3,

title = "Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size",

abstract = "Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GWsignificant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10-8 and rs910316 in TMED10, P-value = 1.4×10-7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10-7 and rs849141 in JAZF1, P-value = 3.2×10-11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10-5 and rs6817306 in LCORL, P-value = 4×10-4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10-4 and rs4911494 at UQCC, P-value = 1.9×10-4), and femur length (including rs710841 at PRKG2, Pvalue = 2.4×10-5 and rs10946808 at HIST1H1D, P-value = 6.4×10-6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.",

author = "Nicole Soranzo and Fernando Rivadeneira and Usha Chinappen-Horsley and Ida Malkina and Richards, {J. Brent} and Naomi Hammond and Lisette Stolk and Alexandra Nica and Michael Inouye and Albert Hofman and Jonathan Stephens and Eleanor Wheeler and Pascal Arp and Rhian Gwilliam and Jhamai, {P. Mila} and Simon Potter and Amy Chaney and Ghori, {Mohammed J.R.} and Radhi Ravindrarajah and Sergey Ermakov and Karol Estrada and Pols, {Huibert A.P.} and Williams, {Frances M.} and McArdle, {Wendy L.} and {Van Meurs}, {Joyce B.} and Loos, {Ruth J.F.} and Dermitzakis, {Emmanouil T.} and Ahmadi, {Kourosh R.} and Hart, {Deborah J.} and Ouwehand, {Willem H.} and Wareham, {Nicholas J.} and In{\^e}s Barroso and Sandhu, {Manjinder S.} and Strachan, {David P.} and Gregory Livshits and Spector, {Timothy D.} and Uitterlinden, {Andr{\'e} G.} and Panos Deloukas",

year = "2009",

month = apr,

doi = "10.1371/journal.pgen.1000445",

language = "אנגלית",

volume = "5",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

}

Soranzo, N, Rivadeneira, F, Chinappen-Horsley, U, Malkina, I, Richards, JB, Hammond, N, Stolk, L, Nica, A, Inouye, M, Hofman, A, Stephens, J, Wheeler, E, Arp, P, Gwilliam, R, Jhamai, PM, Potter, S, Chaney, A, Ghori, MJR, Ravindrarajah, R, Ermakov, S, Estrada, K, Pols, HAP, Williams, FM, McArdle, WL, Van Meurs, JB, Loos, RJF, Dermitzakis, ET, Ahmadi, KR, Hart, DJ, Ouwehand, WH, Wareham, NJ, Barroso, I, Sandhu, MS, Strachan, DP, Livshits, G, Spector, TD, Uitterlinden, AG & Deloukas, P 2009, 'Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size', PLoS Genetics, vol. 5, no. 4. https://doi.org/10.1371/journal.pgen.1000445

TY - JOUR

T1 - Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size

AU - Soranzo, Nicole

AU - Rivadeneira, Fernando

AU - Chinappen-Horsley, Usha

AU - Malkina, Ida

AU - Richards, J. Brent

AU - Hammond, Naomi

AU - Stolk, Lisette

AU - Nica, Alexandra

AU - Inouye, Michael

AU - Hofman, Albert

AU - Stephens, Jonathan

AU - Wheeler, Eleanor

AU - Arp, Pascal

AU - Gwilliam, Rhian

AU - Jhamai, P. Mila

AU - Potter, Simon

AU - Chaney, Amy

AU - Ghori, Mohammed J.R.

AU - Ravindrarajah, Radhi

AU - Ermakov, Sergey

AU - Estrada, Karol

AU - Pols, Huibert A.P.

AU - Williams, Frances M.

AU - McArdle, Wendy L.

AU - Van Meurs, Joyce B.

AU - Loos, Ruth J.F.

AU - Dermitzakis, Emmanouil T.

AU - Ahmadi, Kourosh R.

AU - Hart, Deborah J.

AU - Ouwehand, Willem H.

AU - Wareham, Nicholas J.

AU - Barroso, Inês

AU - Sandhu, Manjinder S.

AU - Strachan, David P.

AU - Livshits, Gregory

AU - Spector, Timothy D.

AU - Uitterlinden, André G.

AU - Deloukas, Panos

PY - 2009/4

Y1 - 2009/4

N2 - Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GWsignificant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10-8 and rs910316 in TMED10, P-value = 1.4×10-7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10-7 and rs849141 in JAZF1, P-value = 3.2×10-11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10-5 and rs6817306 in LCORL, P-value = 4×10-4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10-4 and rs4911494 at UQCC, P-value = 1.9×10-4), and femur length (including rs710841 at PRKG2, Pvalue = 2.4×10-5 and rs10946808 at HIST1H1D, P-value = 6.4×10-6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.

AB - Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GWsignificant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10-8 and rs910316 in TMED10, P-value = 1.4×10-7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10-7 and rs849141 in JAZF1, P-value = 3.2×10-11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10-5 and rs6817306 in LCORL, P-value = 4×10-4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10-4 and rs4911494 at UQCC, P-value = 1.9×10-4), and femur length (including rs710841 at PRKG2, Pvalue = 2.4×10-5 and rs10946808 at HIST1H1D, P-value = 6.4×10-6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.

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Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size

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