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 M.K. Williams; J. Brent Richards; Scott G. Wilson; Tim D. Spector; Benjamin G. Faber; Deborah A. Lawlor; 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

doi:10.1002/jbmr.3605

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 M.K. Williams
, J. Brent Richards
, Scott G. Wilson
, Tim D. Spector
, Benjamin G. Faber
, Deborah A. Lawlor

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

Bar-Ilan University - Azrieli Faculty of Medicine

University of Bristol
California Pacific Medical Center
Department of Medicine
Beth Israel Deaconess Medical Center
Arthritis and Musculoskeletal Medicine
University of Aberdeen
University of Dundee
Broad Institute
Oregon Health and Science University
University of California at Davis
Department of Endocrinology and Diabetes
Sir Charles Gairdner Hospital
School of Biomedical Sciences
University of Western Australia
Department of Twin Research and Genetic Epidemiology
King's College London
Departments of Medicine
McGill University
McGill University
Centre for Bone and Arthritis Research
University of Gothenburg
Department of Pharmacology and Neuroscience
Umeå University
Department of Human Evolutionary Biology
Harvard University
Beck Radiological Innovations
University of Queensland

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

54 Scopus citations

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.

Original language	English
Pages (from-to)	241-251
Number of pages	11
Journal	Journal of Bone and Mineral Research
Volume	34
Issue number	2
DOIs	https://doi.org/10.1002/jbmr.3605
State	Published - Feb 2019

Bibliographical note

Publisher Copyright:
© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Funding

The Umeå Fracture and Osteoporosis Study (UFO) is supported by the Swedish Research Council (K20006-72X-20155013), the Swedish Sports Research Council (87/06), the Swedish Society of Medicine, the Kempe-Foundation (JCK-1021), and by grants from the Medical Faculty of Umeå Unviersity (ALFVLL:968:22-2005, ALFVL:-937-2006, ALFVLL:223:11-2007, and ALFVLL:78151-2009) and from the county council of V€asterbotten (Spjutspetsanslag VLL:159:33-2007). SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. ALSPAC data collection was supported by the Wellcome Trust (grants WT092830M; WT088806; WT102215/2/13/2), UK Medical Research Council (G1001357), and University of Bristol. The UK Medical Research Council and the Wellcome Trust (102215/2/13/ 2) and the University of Bristol provide core support for ALSPAC. TwinsUK: The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/ 2007-2013). The study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. SNP genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. MrOS: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study “Replication of candidate gene associations and bone strength phenotype in MrOS” under the grant number R01 AR051124. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2 AR058973. Framingham Heart Study: The Framingham Osteoporosis Study is supported by grants from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases and the National Institute on Aging (R01 AR41398, R01 AR 061162, R01 AR050066, and R01 AR061445). The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. DK was also supported by Israel Science Foundation grant #1283/14. TDC and DR thank Dr Claire Reardon and the entire Harvard University Bauer Core facility for assistance with ATAC-seq next generation sequencing. This work was funded in part by the Harvard University Milton Fund, NSF (BCS-1518596), and NIH NIAMS (1R01AR070139-01A1) to TDC. This study was funded by Arthritis Research UK project grant 20244, which also provided salary funding for DB and CVG. LP works in the MRC Integrative Epidemiology Unit, a UK MRC-funded unit (MC_ UU_ 12013/4 & MC_UU_12013/5). This study was also supported by the Australian National Health and Medical Research Council (project grants 1048216 and 1127156), the Sir Charles Gairdner Hospital RAC (SGW), and the iVEC/Pawsey Supercomputing Centre (project grants Pawsey0162 and Director2025 [SGW]). The salary of BHM was supported by a Raine Medical Research Foundation Priming Grant.

Funders	Funder number
Australian National Health and Medical Research Council	1048216, 1127156
Harvard University Milton Fund
Kempe-Foundation	JCK-1021
Medical Faculty of Umeå Unviersity	ALFVLL:78151-2009, -937-2006
NIH NIAMS	1R01AR070139-01A1
National Institute of Arthritis, Musculoskeletal, and Skin Diseases
Robert Dawson Evans Endowment
Sir Charles Gairdner Hospital	Director2025, Pawsey0162
Swedish Sports Research Council	87/06
UK Medical Research Council	G1001357
county council of V€asterbotten
National Science Foundation	BCS-1518596
National Institutes of Health	U01 AG027810, RC2 AR058973, U01 AG042140, U01 AG042139, U01 AR066160, U01 AG042124, U01 AG042168, U01 AG042145, UL1 TR000128, R01 AR051124, U01 AG042143
National Institute on Aging	R01 AR35582, R01 AR061445, R01 AG005407, R01 AR 061162, R01 AR050066, R01 AG027576, R01 AR41398, R01 AG005394, R01 AG027574, R01 AR35584
National Heart, Lung, and Blood Institute	N02-HL-6-4278, N01-HC-25195
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01AR035583
National Center for Advancing Translational Sciences
Wellcome Trust	WT088806, WT102215/2/13/2, WT092830M
National Institute for Health Research
Arthritis Research UK	20244
University of Bristol
Raine Medical Research Foundation
Israel Science Foundation	1283/14
Vetenskapsrådet	K20006-72X-20155013
Seventh Framework Programme	FP7/ 2007-2013
Svenska Läkaresällskapet

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

DXA
GWAS
HIP FRACTURE RISK
HIP SHAPE
OSTEOARTHRITIS

Access to Document

10.1002/jbmr.3605

Cite this

Baird, D. A., Evans, D. S., Kamanu, F. K., Gregory, J. S., Saunders, F. R., Giuraniuc, C. V., Barr, R. J., Aspden, R. M., Jenkins, D., Kiel, D. P., Orwoll, E. S., Cummings, S. R., Lane, N. E., Mullin, B. H., Williams, F. M. K., Richards, J. B., Wilson, S. G., Spector, T. D., Faber, B. G., ... Tobias, J. H. (2019). Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies. Journal of Bone and Mineral Research, 34(2), 241-251. https://doi.org/10.1002/jbmr.3605

@article{df41bb4df6bd4c3b84832402ada88db3,

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

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 {\texttimes} 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.",

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.\}",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.",

year = "2019",

month = feb,

doi = "10.1002/jbmr.3605",

language = "אנגלית",

volume = "34",

pages = "241--251",

journal = "Journal of Bone and Mineral Research",

issn = "0884-0431",

publisher = "Oxford University Press",

number = "2",

}

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 2019, 'Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies', Journal of Bone and Mineral Research, vol. 34, no. 2, pp. 241-251. https://doi.org/10.1002/jbmr.3605

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 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.

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.

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.

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KW - GWAS

KW - HIP FRACTURE RISK

KW - HIP SHAPE

KW - OSTEOARTHRITIS

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JO - Journal of Bone and Mineral Research

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IS - 2

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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