Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies

Denis A Baird, Daniel S Evans, Frederick K Kamanu, Jennifer S Gregory, Fiona R Saunders, Claudiu V Giuraniuc, Rebecca J Barr, Richard M Aspden, Deborah Jenkins, Douglas P Kiel, Eric S Orwoll, Steven R Cummings, Nancy E Lane, Benjamin H Mullin, Frances Mk Williams, J Brent Richards, Scott G Wilson, Tim D Spector, Benjamin G Faber, Deborah A Lawlor & 10 others Elin Grundberg, Claes Ohlsson, Ulrika Pettersson-Kymmer, Terence D Capellini, Daniel Richard, Thomas J Beck, David M Evans, Lavinia Paternoster, David Karasik, Jonathan H Tobias

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Abstract

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2  > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Original languageEnglish
Pages (from-to)241-251
Number of pages11
JournalJournal of Bone & Mineral Research
Volume34
Issue number2
DOIs
Publication statusPublished - Feb 2019

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Meta-Analysis
Hip
Hip Osteoarthritis
Osteoporotic Fractures
Photon Absorptiometry
Hip Fractures
Osteogenesis
Femur
Osteoporosis
Chromatin
Single Nucleotide Polymorphism
Minerals
Longitudinal Studies
Software
Extremities
Parents
Bone and Bones
Growth
Research
Genes

Cite this

Baird, D. A., Evans, D. S., Kamanu, F. K., Gregory, J. S., Saunders, F. R., Giuraniuc, C. V., ... Tobias, J. H. (2019). Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies. Journal of Bone & Mineral Research, 34(2), 241-251. https://doi.org/10.1002/jbmr.3605
Baird, Denis A ; Evans, Daniel S ; Kamanu, Frederick K ; Gregory, Jennifer S ; Saunders, Fiona R ; Giuraniuc, Claudiu V ; Barr, Rebecca J ; Aspden, Richard M ; Jenkins, Deborah ; Kiel, Douglas P ; Orwoll, Eric S ; Cummings, Steven R ; Lane, Nancy E ; Mullin, Benjamin H ; Williams, Frances Mk ; Richards, J Brent ; Wilson, Scott G ; Spector, Tim D ; Faber, Benjamin G ; Lawlor, Deborah A ; Grundberg, Elin ; Ohlsson, Claes ; Pettersson-Kymmer, Ulrika ; Capellini, Terence D ; Richard, Daniel ; Beck, Thomas J ; Evans, David M ; Paternoster, Lavinia ; Karasik, David ; Tobias, Jonathan H. / Identification of Novel Loci Associated With Hip Shape : A Meta-Analysis of Genomewide Association Studies. In: Journal of Bone & Mineral Research. 2019 ; Vol. 34, No. 2. pp. 241-251.
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abstract = "We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2  > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. {\circledC} 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.",
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Baird, DA, Evans, DS, Kamanu, FK, Gregory, JS, Saunders, FR, Giuraniuc, CV, Barr, RJ, Aspden, RM, Jenkins, D, Kiel, DP, Orwoll, ES, Cummings, SR, Lane, NE, Mullin, BH, Williams, FM, Richards, JB, Wilson, SG, Spector, TD, Faber, BG, Lawlor, DA, Grundberg, E, Ohlsson, C, Pettersson-Kymmer, U, Capellini, TD, Richard, D, Beck, TJ, Evans, DM, Paternoster, L, Karasik, D & Tobias, JH 2019, 'Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies' Journal of Bone & Mineral Research, vol. 34, no. 2, pp. 241-251. https://doi.org/10.1002/jbmr.3605

Identification of Novel Loci Associated With Hip Shape : A Meta-Analysis of Genomewide Association Studies. / Baird, Denis A; Evans, Daniel S; Kamanu, Frederick K; Gregory, Jennifer S; Saunders, Fiona R; Giuraniuc, Claudiu V; Barr, Rebecca J; Aspden, Richard M; Jenkins, Deborah; Kiel, Douglas P; Orwoll, Eric S; Cummings, Steven R; Lane, Nancy E; Mullin, Benjamin H; Williams, Frances Mk; Richards, J Brent; Wilson, Scott G; Spector, Tim D; Faber, Benjamin G; Lawlor, Deborah A; Grundberg, Elin; Ohlsson, Claes; Pettersson-Kymmer, Ulrika; Capellini, Terence D; Richard, Daniel; Beck, Thomas J; Evans, David M; Paternoster, Lavinia; Karasik, David; Tobias, Jonathan H.

In: Journal of Bone & Mineral Research, Vol. 34, No. 2, 02.2019, p. 241-251.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of Novel Loci Associated With Hip Shape

T2 - A Meta-Analysis of Genomewide Association Studies

AU - Baird, Denis A

AU - Evans, Daniel S

AU - Kamanu, Frederick K

AU - Gregory, Jennifer S

AU - Saunders, Fiona R

AU - Giuraniuc, Claudiu V

AU - Barr, Rebecca J

AU - Aspden, Richard M

AU - Jenkins, Deborah

AU - Kiel, Douglas P

AU - Orwoll, Eric S

AU - Cummings, Steven R

AU - Lane, Nancy E

AU - Mullin, Benjamin H

AU - Williams, Frances Mk

AU - Richards, J Brent

AU - Wilson, Scott G

AU - Spector, Tim D

AU - Faber, Benjamin G

AU - Lawlor, Deborah A

AU - Grundberg, Elin

AU - Ohlsson, Claes

AU - Pettersson-Kymmer, Ulrika

AU - Capellini, Terence D

AU - Richard, Daniel

AU - Beck, Thomas J

AU - Evans, David M

AU - Paternoster, Lavinia

AU - Karasik, David

AU - Tobias, Jonathan H

PY - 2019/2

Y1 - 2019/2

N2 - We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2  > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

AB - We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2  > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

U2 - 10.1002/jbmr.3605

DO - 10.1002/jbmr.3605

M3 - Article

VL - 34

SP - 241

EP - 251

JO - Journal of Bone & Mineral Research

JF - Journal of Bone & Mineral Research

SN - 0884-0431

IS - 2

ER -