Genome-wide association study meta-analysis for quantitative ultrasound parameters of bone identifies five novel loci for broadband ultrasound attenuation

Benjamin H Mullin, Jing Hua Zhao, Suzanne Brown, John R B Perry, Jian'An Luan, Hou-Feng Zheng, Claudia Langenberg, Frank Dudbridge, Robert A. Scott, Nick J Wareham, Tim D Spector, J Brent Richards, John P Walsh, Scott G Wilson

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Abstract

Osteoporosis is a common and debilitating bone disease that is characterised by low bone mineral density, typically assessed using dual-energy X-ray absorptiometry. Quantitative ultrasound (QUS), commonly utilising the two parameters velocity of sound (VOS) and broadband ultrasound attenuation (BUA), is an alternative technology used to assess bone properties at peripheral skeletal sites. The genetic influence on the bone qualities assessed by QUS remains an under-studied area. We performed a comprehensive GWAS including low-frequency variants (MAF ≥0.005) for BUA and VOS using a discovery population of individuals with whole-genome sequence (WGS) data from the UK10K project (n=1,268). These results were then meta-analysed with those from two deeply imputed GWAS replication cohorts (n=1,610 and 13,749). In the gender-combined analysis, we identified eight loci associated with BUA and five with VOS at the genome-wide significance level, including three novel loci for BUA at 8p23.1 (PPP1R3B), 11q23.1 (LOC387810) and 22q11.21 (SEPT5) (P = 2.4 × 10-8-1.6 × 10-9). Gene-based association testing in the gender-combined dataset revealed eight loci associated with BUA and seven with VOS at the genome-wide significance level, with one novel locus for BUA at FAM167A (8p23.1) (P = 1.4 × 10-6). An additional novel locus for BUA was seen in the male-specific analysis at DEFB103B (8p23.1) (P = 1.8 × 10-6). Fracture analysis revealed significant associations between variation at the WNT16 and RSPO3 loci and fracture risk (P = 0.004 and 4.0 × 10-4 respectively). In conclusion, by performing a large GWAS meta-analysis for QUS parameters of bone using a combination of WGS and deeply imputed genotype data, we have identified five novel genetic loci associated with BUA.

Original languageEnglish
Pages (from-to)2791-2802
JournalHuman Molecular Genetics
Volume26
Issue number14
DOIs
Publication statusPublished - 15 Jul 2017

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Genome-Wide Association Study
Meta-Analysis
Genome
Bone and Bones
Genetic Loci
Bone Diseases
Photon Absorptiometry
Bone Density
Osteoporosis
Genotype
Technology
Population
Genes

Cite this

Mullin, Benjamin H ; Hua Zhao, Jing ; Brown, Suzanne ; Perry, John R B ; Luan, Jian'An ; Zheng, Hou-Feng ; Langenberg, Claudia ; Dudbridge, Frank ; Scott, Robert A. ; Wareham, Nick J ; Spector, Tim D ; Brent Richards, J ; Walsh, John P ; Wilson, Scott G. / Genome-wide association study meta-analysis for quantitative ultrasound parameters of bone identifies five novel loci for broadband ultrasound attenuation. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 14. pp. 2791-2802.
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abstract = "Osteoporosis is a common and debilitating bone disease that is characterised by low bone mineral density, typically assessed using dual-energy X-ray absorptiometry. Quantitative ultrasound (QUS), commonly utilising the two parameters velocity of sound (VOS) and broadband ultrasound attenuation (BUA), is an alternative technology used to assess bone properties at peripheral skeletal sites. The genetic influence on the bone qualities assessed by QUS remains an under-studied area. We performed a comprehensive GWAS including low-frequency variants (MAF ≥0.005) for BUA and VOS using a discovery population of individuals with whole-genome sequence (WGS) data from the UK10K project (n=1,268). These results were then meta-analysed with those from two deeply imputed GWAS replication cohorts (n=1,610 and 13,749). In the gender-combined analysis, we identified eight loci associated with BUA and five with VOS at the genome-wide significance level, including three novel loci for BUA at 8p23.1 (PPP1R3B), 11q23.1 (LOC387810) and 22q11.21 (SEPT5) (P = 2.4 × 10-8-1.6 × 10-9). Gene-based association testing in the gender-combined dataset revealed eight loci associated with BUA and seven with VOS at the genome-wide significance level, with one novel locus for BUA at FAM167A (8p23.1) (P = 1.4 × 10-6). An additional novel locus for BUA was seen in the male-specific analysis at DEFB103B (8p23.1) (P = 1.8 × 10-6). Fracture analysis revealed significant associations between variation at the WNT16 and RSPO3 loci and fracture risk (P = 0.004 and 4.0 × 10-4 respectively). In conclusion, by performing a large GWAS meta-analysis for QUS parameters of bone using a combination of WGS and deeply imputed genotype data, we have identified five novel genetic loci associated with BUA.",
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author = "Mullin, {Benjamin H} and {Hua Zhao}, Jing and Suzanne Brown and Perry, {John R B} and Jian'An Luan and Hou-Feng Zheng and Claudia Langenberg and Frank Dudbridge and Scott, {Robert A.} and Wareham, {Nick J} and Spector, {Tim D} and {Brent Richards}, J and Walsh, {John P} and Wilson, {Scott G}",
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Mullin, BH, Hua Zhao, J, Brown, S, Perry, JRB, Luan, JA, Zheng, H-F, Langenberg, C, Dudbridge, F, Scott, RA, Wareham, NJ, Spector, TD, Brent Richards, J, Walsh, JP & Wilson, SG 2017, 'Genome-wide association study meta-analysis for quantitative ultrasound parameters of bone identifies five novel loci for broadband ultrasound attenuation' Human Molecular Genetics, vol. 26, no. 14, pp. 2791-2802. https://doi.org/10.1093/hmg/ddx174

Genome-wide association study meta-analysis for quantitative ultrasound parameters of bone identifies five novel loci for broadband ultrasound attenuation. / Mullin, Benjamin H; Hua Zhao, Jing; Brown, Suzanne; Perry, John R B; Luan, Jian'An; Zheng, Hou-Feng; Langenberg, Claudia; Dudbridge, Frank; Scott, Robert A.; Wareham, Nick J; Spector, Tim D; Brent Richards, J; Walsh, John P; Wilson, Scott G.

In: Human Molecular Genetics, Vol. 26, No. 14, 15.07.2017, p. 2791-2802.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study meta-analysis for quantitative ultrasound parameters of bone identifies five novel loci for broadband ultrasound attenuation

AU - Mullin, Benjamin H

AU - Hua Zhao, Jing

AU - Brown, Suzanne

AU - Perry, John R B

AU - Luan, Jian'An

AU - Zheng, Hou-Feng

AU - Langenberg, Claudia

AU - Dudbridge, Frank

AU - Scott, Robert A.

AU - Wareham, Nick J

AU - Spector, Tim D

AU - Brent Richards, J

AU - Walsh, John P

AU - Wilson, Scott G

N1 - © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2017/7/15

Y1 - 2017/7/15

N2 - Osteoporosis is a common and debilitating bone disease that is characterised by low bone mineral density, typically assessed using dual-energy X-ray absorptiometry. Quantitative ultrasound (QUS), commonly utilising the two parameters velocity of sound (VOS) and broadband ultrasound attenuation (BUA), is an alternative technology used to assess bone properties at peripheral skeletal sites. The genetic influence on the bone qualities assessed by QUS remains an under-studied area. We performed a comprehensive GWAS including low-frequency variants (MAF ≥0.005) for BUA and VOS using a discovery population of individuals with whole-genome sequence (WGS) data from the UK10K project (n=1,268). These results were then meta-analysed with those from two deeply imputed GWAS replication cohorts (n=1,610 and 13,749). In the gender-combined analysis, we identified eight loci associated with BUA and five with VOS at the genome-wide significance level, including three novel loci for BUA at 8p23.1 (PPP1R3B), 11q23.1 (LOC387810) and 22q11.21 (SEPT5) (P = 2.4 × 10-8-1.6 × 10-9). Gene-based association testing in the gender-combined dataset revealed eight loci associated with BUA and seven with VOS at the genome-wide significance level, with one novel locus for BUA at FAM167A (8p23.1) (P = 1.4 × 10-6). An additional novel locus for BUA was seen in the male-specific analysis at DEFB103B (8p23.1) (P = 1.8 × 10-6). Fracture analysis revealed significant associations between variation at the WNT16 and RSPO3 loci and fracture risk (P = 0.004 and 4.0 × 10-4 respectively). In conclusion, by performing a large GWAS meta-analysis for QUS parameters of bone using a combination of WGS and deeply imputed genotype data, we have identified five novel genetic loci associated with BUA.

AB - Osteoporosis is a common and debilitating bone disease that is characterised by low bone mineral density, typically assessed using dual-energy X-ray absorptiometry. Quantitative ultrasound (QUS), commonly utilising the two parameters velocity of sound (VOS) and broadband ultrasound attenuation (BUA), is an alternative technology used to assess bone properties at peripheral skeletal sites. The genetic influence on the bone qualities assessed by QUS remains an under-studied area. We performed a comprehensive GWAS including low-frequency variants (MAF ≥0.005) for BUA and VOS using a discovery population of individuals with whole-genome sequence (WGS) data from the UK10K project (n=1,268). These results were then meta-analysed with those from two deeply imputed GWAS replication cohorts (n=1,610 and 13,749). In the gender-combined analysis, we identified eight loci associated with BUA and five with VOS at the genome-wide significance level, including three novel loci for BUA at 8p23.1 (PPP1R3B), 11q23.1 (LOC387810) and 22q11.21 (SEPT5) (P = 2.4 × 10-8-1.6 × 10-9). Gene-based association testing in the gender-combined dataset revealed eight loci associated with BUA and seven with VOS at the genome-wide significance level, with one novel locus for BUA at FAM167A (8p23.1) (P = 1.4 × 10-6). An additional novel locus for BUA was seen in the male-specific analysis at DEFB103B (8p23.1) (P = 1.8 × 10-6). Fracture analysis revealed significant associations between variation at the WNT16 and RSPO3 loci and fracture risk (P = 0.004 and 4.0 × 10-4 respectively). In conclusion, by performing a large GWAS meta-analysis for QUS parameters of bone using a combination of WGS and deeply imputed genotype data, we have identified five novel genetic loci associated with BUA.

KW - Journal Article

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DO - 10.1093/hmg/ddx174

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SP - 2791

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JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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