Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry

Yi Hsiang Hsu; Karol Estrada; Evangelos Evangelou; Cheryl Ackert-Bicknell; Kristina Akesson; Thomas Beck; Suzanne J. Brown; Terence Capellini; Laura Carbone; Jane Cauley; Ching Lung Cheung; Steven R. Cummings; Stefan Czerwinski; Serkalem Demissie; Michael Econs; Daniel Evans; Charles Farber; Kaare Gautvik; Tamara Harris; Candace Kammerer; John Kemp; Daniel L. Koller; Annie Kung; Debbie Lawlor; Miryoung Lee; Mattias Lorentzon; Fiona McGuigan; Carolina Medina-Gomez; Braxton Mitchell; Anne Newman; Carrie Nielson; Claes Ohlsson; Munro Peacock; Sjur Reppe; J. Brent Richards; John Robbins; Gunnar Sigurdsson; Timothy D. Spector; Kari Stefansson; Elizabeth Streeten; Unnur Styrkarsdottir; Jonathan Tobias; Katerina Trajanoska; André Uitterlinden; Liesbeth Vandenput; Scott G. Wilson; Laura Yerges-Armstrong; Mariel Young; M. Carola Zillikens; Fernando Rivadeneira; Douglas P. Kiel; David Karasik

doi:10.1002/jbmr.3698

Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry

Yi Hsiang Hsu, Karol Estrada, Evangelos Evangelou, Cheryl Ackert-Bicknell, Kristina Akesson, Thomas Beck, Suzanne J. Brown, Terence Capellini, Laura Carbone, Jane Cauley, Ching Lung Cheung, Steven R. Cummings, Stefan Czerwinski, Serkalem Demissie, Michael Econs, Daniel Evans, Charles Farber, Kaare Gautvik, Tamara Harris, Candace KammererJohn Kemp, Daniel L. Koller, Annie Kung, Debbie Lawlor, Miryoung Lee, Mattias Lorentzon, Fiona McGuigan, Carolina Medina-Gomez, Braxton Mitchell, Anne Newman, Carrie Nielson, Claes Ohlsson, Munro Peacock, Sjur Reppe, J. Brent Richards, John Robbins, Gunnar Sigurdsson, Timothy D. Spector, Kari Stefansson, Elizabeth Streeten, Unnur Styrkarsdottir, Jonathan Tobias, Katerina Trajanoska, André Uitterlinden, Liesbeth Vandenput, Scott G. Wilson, Laura Yerges-Armstrong, Mariel Young, M. Carola Zillikens, Fernando Rivadeneira, Douglas P. Kiel, David Karasik^*

^*Corresponding author for this work

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Abstract

Hip geometry (HG) is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: 1) Femoral neck length; 2) Neck-shaft angle; 3) Femoral neck width, and 4) Femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16-93 years. Association analyses were performed with ~ 2.5 million polymorphisms
under an additive model adjusted for age and body mass index; an additional analysis also adjusted for height. Replication analyses of meta-GWAS significant loci (at genome-wide significance, GWS, threshold p≤5x10-8) were performed in 7 additional cohorts in-silico. In meta-analysis not adjusting for height (combined Discovery and Replication stages), GWS associations were found on chr. 4 (in HHIP), chr. 8 (C8orf34), chr. 13 (FAM10A4 and DLEU2), and chr. 20 (in
DDX27). The height-adjusted meta-analysis showed significant associations at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several HG signals overlapped with bone mineral density (BMD), including JAG1 on chr. 20, near TNFRSF11B (chr. 8), SOX6 and LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 x 10-5). We used bone transcriptome data and discovered
several significant eQTLs, including rs7102273 and PPP6R3 expression (p=0.0007), and rs6556301 (intergenic, chr.5) and PDLIM7 expression
(p=0.005).

In conclusion, we found associations between HG measures and several genes being part of biological pathways relevant to BMD and fractures. The results provide a defined set of genes facilitating further experimental exploration and validation to understand biological mechanisms underlying human bone geometry and etiology of bone fragility.

Original language	English
Article number	e3698
Pages (from-to)	1284-1296
Number of pages	13
Journal	Journal of Bone and Mineral Research
Volume	34
Issue number	7
Early online date	19 Mar 2019
DOIs	https://doi.org/10.1002/jbmr.3698
Publication status	Published - 1 Jul 2019

Keywords

DXA
Analysis/quantitation of bone
osteoporosis
diseases and sisorders of/related to bone
human association studies
genetic research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hsu, Y. H., Estrada, K., Evangelou, E., Ackert-Bicknell, C., Akesson, K., Beck, T., Brown, S. J., Capellini, T., Carbone, L., Cauley, J., Cheung, C. L., Cummings, S. R., Czerwinski, S., Demissie, S., Econs, M., Evans, D., Farber, C., Gautvik, K., Harris, T., ... Karasik, D. (2019). Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry. Journal of Bone and Mineral Research, 34(7), 1284-1296. Article e3698. https://doi.org/10.1002/jbmr.3698

@article{7de48e12527446e4889226bf83bce9fb,

title = "Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry",

abstract = "Hip geometry (HG) is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: 1) Femoral neck length; 2) Neck-shaft angle; 3) Femoral neck width, and 4) Femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16-93 years. Association analyses were performed with ~ 2.5 million polymorphismsunder an additive model adjusted for age and body mass index; an additional analysis also adjusted for height. Replication analyses of meta-GWAS significant loci (at genome-wide significance, GWS, threshold p≤5x10-8) were performed in 7 additional cohorts in-silico. In meta-analysis not adjusting for height (combined Discovery and Replication stages), GWS associations were found on chr. 4 (in HHIP), chr. 8 (C8orf34), chr. 13 (FAM10A4 and DLEU2), and chr. 20 (inDDX27). The height-adjusted meta-analysis showed significant associations at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several HG signals overlapped with bone mineral density (BMD), including JAG1 on chr. 20, near TNFRSF11B (chr. 8), SOX6 and LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 x 10-5). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p=0.0007), and rs6556301 (intergenic, chr.5) and PDLIM7 expression(p=0.005). In conclusion, we found associations between HG measures and several genes being part of biological pathways relevant to BMD and fractures. The results provide a defined set of genes facilitating further experimental exploration and validation to understand biological mechanisms underlying human bone geometry and etiology of bone fragility.",

keywords = "DXA, Analysis/quantitation of bone, osteoporosis, diseases and sisorders of/related to bone, human association studies, genetic research",

author = "Hsu, {Yi Hsiang} and Karol Estrada and Evangelos Evangelou and Cheryl Ackert-Bicknell and Kristina Akesson and Thomas Beck and Brown, {Suzanne J.} and Terence Capellini and Laura Carbone and Jane Cauley and Cheung, {Ching Lung} and Cummings, {Steven R.} and Stefan Czerwinski and Serkalem Demissie and Michael Econs and Daniel Evans and Charles Farber and Kaare Gautvik and Tamara Harris and Candace Kammerer and John Kemp and Koller, {Daniel L.} and Annie Kung and Debbie Lawlor and Miryoung Lee and Mattias Lorentzon and Fiona McGuigan and Carolina Medina-Gomez and Braxton Mitchell and Anne Newman and Carrie Nielson and Claes Ohlsson and Munro Peacock and Sjur Reppe and Richards, {J. Brent} and John Robbins and Gunnar Sigurdsson and Spector, {Timothy D.} and Kari Stefansson and Elizabeth Streeten and Unnur Styrkarsdottir and Jonathan Tobias and Katerina Trajanoska and Andr{\'e} Uitterlinden and Liesbeth Vandenput and Wilson, {Scott G.} and Laura Yerges-Armstrong and Mariel Young and Zillikens, {M. Carola} and Fernando Rivadeneira and Kiel, {Douglas P.} and David Karasik",

year = "2019",

month = jul,

day = "1",

doi = "10.1002/jbmr.3698",

language = "English",

volume = "34",

pages = "1284--1296",

journal = "Journal of Bone and Mineral Research",

issn = "0884-0431",

publisher = "Wiley",

number = "7",

}

Hsu, YH, Estrada, K, Evangelou, E, Ackert-Bicknell, C, Akesson, K, Beck, T, Brown, SJ, Capellini, T, Carbone, L, Cauley, J, Cheung, CL, Cummings, SR, Czerwinski, S, Demissie, S, Econs, M, Evans, D, Farber, C, Gautvik, K, Harris, T, Kammerer, C, Kemp, J, Koller, DL, Kung, A, Lawlor, D, Lee, M, Lorentzon, M, McGuigan, F, Medina-Gomez, C, Mitchell, B, Newman, A, Nielson, C, Ohlsson, C, Peacock, M, Reppe, S, Richards, JB, Robbins, J, Sigurdsson, G, Spector, TD, Stefansson, K, Streeten, E, Styrkarsdottir, U, Tobias, J, Trajanoska, K, Uitterlinden, A, Vandenput, L, Wilson, SG, Yerges-Armstrong, L, Young, M, Zillikens, MC, Rivadeneira, F, Kiel, DP & Karasik, D 2019, 'Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry', Journal of Bone and Mineral Research, vol. 34, no. 7, e3698, pp. 1284-1296. https://doi.org/10.1002/jbmr.3698

TY - JOUR

T1 - Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry

AU - Hsu, Yi Hsiang

AU - Estrada, Karol

AU - Evangelou, Evangelos

AU - Ackert-Bicknell, Cheryl

AU - Akesson, Kristina

AU - Beck, Thomas

AU - Brown, Suzanne J.

AU - Capellini, Terence

AU - Carbone, Laura

AU - Cauley, Jane

AU - Cheung, Ching Lung

AU - Cummings, Steven R.

AU - Czerwinski, Stefan

AU - Demissie, Serkalem

AU - Econs, Michael

AU - Evans, Daniel

AU - Farber, Charles

AU - Gautvik, Kaare

AU - Harris, Tamara

AU - Kammerer, Candace

AU - Kemp, John

AU - Koller, Daniel L.

AU - Kung, Annie

AU - Lawlor, Debbie

AU - Lee, Miryoung

AU - Lorentzon, Mattias

AU - McGuigan, Fiona

AU - Medina-Gomez, Carolina

AU - Mitchell, Braxton

AU - Newman, Anne

AU - Nielson, Carrie

AU - Ohlsson, Claes

AU - Peacock, Munro

AU - Reppe, Sjur

AU - Richards, J. Brent

AU - Robbins, John

AU - Sigurdsson, Gunnar

AU - Spector, Timothy D.

AU - Stefansson, Kari

AU - Streeten, Elizabeth

AU - Styrkarsdottir, Unnur

AU - Tobias, Jonathan

AU - Trajanoska, Katerina

AU - Uitterlinden, André

AU - Vandenput, Liesbeth

AU - Wilson, Scott G.

AU - Yerges-Armstrong, Laura

AU - Young, Mariel

AU - Zillikens, M. Carola

AU - Rivadeneira, Fernando

AU - Kiel, Douglas P.

AU - Karasik, David

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Hip geometry (HG) is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: 1) Femoral neck length; 2) Neck-shaft angle; 3) Femoral neck width, and 4) Femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16-93 years. Association analyses were performed with ~ 2.5 million polymorphismsunder an additive model adjusted for age and body mass index; an additional analysis also adjusted for height. Replication analyses of meta-GWAS significant loci (at genome-wide significance, GWS, threshold p≤5x10-8) were performed in 7 additional cohorts in-silico. In meta-analysis not adjusting for height (combined Discovery and Replication stages), GWS associations were found on chr. 4 (in HHIP), chr. 8 (C8orf34), chr. 13 (FAM10A4 and DLEU2), and chr. 20 (inDDX27). The height-adjusted meta-analysis showed significant associations at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several HG signals overlapped with bone mineral density (BMD), including JAG1 on chr. 20, near TNFRSF11B (chr. 8), SOX6 and LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 x 10-5). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p=0.0007), and rs6556301 (intergenic, chr.5) and PDLIM7 expression(p=0.005). In conclusion, we found associations between HG measures and several genes being part of biological pathways relevant to BMD and fractures. The results provide a defined set of genes facilitating further experimental exploration and validation to understand biological mechanisms underlying human bone geometry and etiology of bone fragility.

AB - Hip geometry (HG) is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: 1) Femoral neck length; 2) Neck-shaft angle; 3) Femoral neck width, and 4) Femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16-93 years. Association analyses were performed with ~ 2.5 million polymorphismsunder an additive model adjusted for age and body mass index; an additional analysis also adjusted for height. Replication analyses of meta-GWAS significant loci (at genome-wide significance, GWS, threshold p≤5x10-8) were performed in 7 additional cohorts in-silico. In meta-analysis not adjusting for height (combined Discovery and Replication stages), GWS associations were found on chr. 4 (in HHIP), chr. 8 (C8orf34), chr. 13 (FAM10A4 and DLEU2), and chr. 20 (inDDX27). The height-adjusted meta-analysis showed significant associations at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several HG signals overlapped with bone mineral density (BMD), including JAG1 on chr. 20, near TNFRSF11B (chr. 8), SOX6 and LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 x 10-5). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p=0.0007), and rs6556301 (intergenic, chr.5) and PDLIM7 expression(p=0.005). In conclusion, we found associations between HG measures and several genes being part of biological pathways relevant to BMD and fractures. The results provide a defined set of genes facilitating further experimental exploration and validation to understand biological mechanisms underlying human bone geometry and etiology of bone fragility.

KW - DXA

KW - Analysis/quantitation of bone

KW - osteoporosis

KW - diseases and sisorders of/related to bone

KW - human association studies

KW - genetic research

UR - http://www.scopus.com/inward/record.url?scp=85063162256&partnerID=8YFLogxK

U2 - 10.1002/jbmr.3698

DO - 10.1002/jbmr.3698

M3 - Article (Academic Journal)

C2 - 30888730

AN - SCOPUS:85063162256

SN - 0884-0431

VL - 34

SP - 1284

EP - 1296

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 7

M1 - e3698

ER -

Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry

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Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry

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