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 D 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, Carola Zillikens, Fernando Rivadeneira, Douglas P. Kiel, David Karasik

Research output: Contribution to journalArticle

Abstract

Hip geometry 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: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) 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 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10–8) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 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 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility.

Original languageEnglish (US)
Pages (from-to)1284-1296
Number of pages13
JournalJournal of Bone and Mineral Research
Volume34
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

Pelvic Bones
Genetic Association Studies
Meta-Analysis
Hip
Femur Neck
Bone Density
Genome-Wide Association Study
Single Nucleotide Polymorphism
Phenotype
Bone and Bones
Bone Fractures
Photon Absorptiometry
Transcriptome
Computer Simulation
Femur
Genes
Body Mass Index
Cohort Studies
Neck

Keywords

  • CANDIDATE GENES
  • FRACTURE, GENOMEWIDE ASSOCIATION STUDY
  • HIP BONE GEOMETRY
  • META-ANALYSIS
  • POLYMORPHISMS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Hsu, Y. H., Estrada, K., Evangelou, E., Ackert-Bicknell, C., Akesson, K., Beck, 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. https://doi.org/10.1002/jbmr.3698

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

In: Journal of Bone and Mineral Research, Vol. 34, No. 7, 01.07.2019, p. 1284-1296.

Research output: Contribution to journalArticle

Hsu, YH, Estrada, K, Evangelou, E, Ackert-Bicknell, C, Akesson, K, Beck, T, Brown, SJ, Capellini, T, Carbone, LD, 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, C, 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, pp. 1284-1296. https://doi.org/10.1002/jbmr.3698
Hsu, Yi Hsiang ; Estrada, Karol ; Evangelou, Evangelos ; Ackert-Bicknell, Cheryl ; Akesson, Kristina ; Beck, Thomas ; Brown, Suzanne J. ; Capellini, Terence ; Carbone, Laura D ; Cauley, Jane ; Cheung, Ching Lung ; Cummings, Steven R. ; Czerwinski, Stefan ; Demissie, Serkalem ; Econs, Michael ; Evans, Daniel ; Farber, Charles ; Gautvik, Kaare ; Harris, Tamara ; Kammerer, Candace ; Kemp, John ; Koller, Daniel L. ; Kung, Annie ; Lawlor, Debbie ; Lee, Miryoung ; Lorentzon, Mattias ; McGuigan, Fiona ; Medina-Gomez, Carolina ; Mitchell, Braxton ; Newman, Anne ; Nielson, Carrie ; Ohlsson, Claes ; Peacock, Munro ; Reppe, Sjur ; Richards, J. Brent ; Robbins, John ; Sigurdsson, Gunnar ; Spector, Timothy D. ; Stefansson, Kari ; Streeten, Elizabeth ; Styrkarsdottir, Unnur ; Tobias, Jonathan ; Trajanoska, Katerina ; Uitterlinden, André ; Vandenput, Liesbeth ; Wilson, Scott G. ; Yerges-Armstrong, Laura ; Young, Mariel ; Zillikens, Carola ; Rivadeneira, Fernando ; Kiel, Douglas P. ; Karasik, David. / Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry. In: Journal of Bone and Mineral Research. 2019 ; Vol. 34, No. 7. pp. 1284-1296.
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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 D

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, Carola

AU - Rivadeneira, Fernando

AU - Kiel, Douglas P.

AU - Karasik, David

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Hip geometry 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: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) 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 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10–8) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 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 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility.

AB - Hip geometry 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: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) 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 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10–8) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 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 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility.

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KW - FRACTURE, GENOMEWIDE ASSOCIATION STUDY

KW - HIP BONE GEOMETRY

KW - META-ANALYSIS

KW - POLYMORPHISMS

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