Identification of novel loci associated with hip shape

a meta-analysis of genome-wide 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 M. K. 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 (r 2 > 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.

Original languageEnglish
JournalJournal of Bone and Mineral Research
Early online date15 Oct 2018
DOIs
Publication statusE-pub ahead of print - 15 Oct 2018

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Hip
Hip Osteoarthritis
Osteoporotic Fractures
Photon Absorptiometry
Hip Fractures
Osteogenesis
Femur
Osteoporosis
Chromatin
Single Nucleotide Polymorphism
Longitudinal Studies
Software
Extremities
Parents
Growth
Genes

Keywords

  • DXA
  • GWAS
  • HIP FRACTURE RISK
  • HIP SHAPE
  • OSTEOARTHRITIS

Cite this

Baird, D. A., Evans, D. S., Kamanu, F. K., Gregory, J. S., Saunders, F. R., Giuraniuc, C. V., ... Tobias, J. H. (2018). Identification of novel loci associated with hip shape: a meta-analysis of genome-wide association studies. Journal of Bone and Mineral Research. 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 M. K. ; 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 genome-wide association studies. In: Journal of Bone and Mineral Research. 2018.
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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 (r 2 > 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.",
keywords = "DXA, GWAS, HIP FRACTURE RISK, HIP SHAPE, OSTEOARTHRITIS",
author = "Baird, {Denis A.} and Evans, {Daniel S.} and Kamanu, {Frederick K.} and Gregory, {Jennifer S.} and Saunders, {Fiona R.} and Giuraniuc, {Claudiu V.} and Barr, {Rebecca J.} and Aspden, {Richard M.} and Deborah Jenkins and Kiel, {Douglas P.} and Orwoll, {Eric S.} and Cummings, {Steven R.} and Lane, {Nancy E.} and Mullin, {Benjamin H.} and Williams, {Frances M. K.} and Richards, {J. Brent} and Wilson, {Scott G.} and Spector, {Tim D.} and Faber, {Benjamin G.} and Lawlor, {Deborah A.} and Elin Grundberg and Claes Ohlsson and Ulrika Pettersson-Kymmer and Capellini, {Terence D.} and Daniel Richard and Beck, {Thomas J.} and Evans, {David M.} and Lavinia Paternoster and David Karasik and Tobias, {Jonathan H.}",
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year = "2018",
month = "10",
day = "15",
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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, FMK, 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 2018, 'Identification of novel loci associated with hip shape: a meta-analysis of genome-wide association studies', Journal of Bone and Mineral Research. https://doi.org/10.1002/jbmr.3605

Identification of novel loci associated with hip shape : a meta-analysis of genome-wide 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 M. K.; 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. (Lead / Corresponding author).

In: Journal of Bone and Mineral Research, 15.10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of novel loci associated with hip shape

T2 - a meta-analysis of genome-wide 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 M. K.

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.

N1 - This article is protected by copyright. All rights reserved.

PY - 2018/10/15

Y1 - 2018/10/15

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 (r 2 > 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.

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 (r 2 > 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.

KW - DXA

KW - GWAS

KW - HIP FRACTURE RISK

KW - HIP SHAPE

KW - OSTEOARTHRITIS

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U2 - 10.1002/jbmr.3605

DO - 10.1002/jbmr.3605

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JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

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