Abstract

The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of bone-mineral density and may be used to predict risk of osteoporotic fracture. We conducted a genome-wide association study (GWAS) for SI using 7,742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2,955). Approximately 6.1 million SNPs were subjected to association analysis, and SI-associated variants were identified. We further conducted meta-analysis of Taiwan Biobank significant SNPs with a Korean population-based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein-protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single-nucleotide polymorphisms (SNPs) within three loci, 7q31.31, 17p13.3 and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank eBMD GWAS, and these three cytobands were replicated successfully after meta-analysis with Korean population cohort as well. However, two SNPs were not replicated. Further studies in larger East Asian populations are needed. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI-associated SNPs as well as two novel SI-related genes. Overall, these results provided further insight into the genetic architecture of osteoporosis. This article is protected by copyright. All rights reserved.

Original languageEnglish
Article numbere3703
Pages (from-to)e3703
JournalJournal of Bone and Mineral Research
DOIs
Publication statusE-pub ahead of print - Feb 19 2019

Fingerprint

Calcaneus
Genome-Wide Association Study
Single Nucleotide Polymorphism
Meta-Analysis
Taiwan
Population
Genes
Gene Ontology
Osteoporotic Fractures
Quantitative Trait Loci
Epigenomics
Bone Density
Osteoporosis
Proteins

Keywords

  • GENOME-WIDE ASSOCIATION STUDY
  • HEEL BONE MINERAL DENSITY
  • OSTEOPOROSIS
  • STIFFNESS INDEX
  • TAIWAN BIOBANK

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Meta-Analysis of Genome-Wide Association Studies Identifies Three Loci Associated With Stiffness Index of the Calcaneus. / Lu, Hsing-Fang; Hung, Kuo-Sheng; Chu, Hou-Wei; Wong, Henry Sung-Ching; Kim, Jihye; Choi, Bo Youl; Kim, Mi Kyung; Tai, Yu-Ting; Ikegawa, Shiro; Cho, Er-Chieh; Chang, Wei-Chiao.

In: Journal of Bone and Mineral Research, 19.02.2019, p. e3703.

Research output: Contribution to journalArticle

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title = "Meta-Analysis of Genome-Wide Association Studies Identifies Three Loci Associated With Stiffness Index of the Calcaneus",
abstract = "The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of bone-mineral density and may be used to predict risk of osteoporotic fracture. We conducted a genome-wide association study (GWAS) for SI using 7,742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2,955). Approximately 6.1 million SNPs were subjected to association analysis, and SI-associated variants were identified. We further conducted meta-analysis of Taiwan Biobank significant SNPs with a Korean population-based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein-protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single-nucleotide polymorphisms (SNPs) within three loci, 7q31.31, 17p13.3 and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank eBMD GWAS, and these three cytobands were replicated successfully after meta-analysis with Korean population cohort as well. However, two SNPs were not replicated. Further studies in larger East Asian populations are needed. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI-associated SNPs as well as two novel SI-related genes. Overall, these results provided further insight into the genetic architecture of osteoporosis. This article is protected by copyright. All rights reserved.",
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AU - Lu, Hsing-Fang

AU - Hung, Kuo-Sheng

AU - Chu, Hou-Wei

AU - Wong, Henry Sung-Ching

AU - Kim, Jihye

AU - Choi, Bo Youl

AU - Kim, Mi Kyung

AU - Tai, Yu-Ting

AU - Ikegawa, Shiro

AU - Cho, Er-Chieh

AU - Chang, Wei-Chiao

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N2 - The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of bone-mineral density and may be used to predict risk of osteoporotic fracture. We conducted a genome-wide association study (GWAS) for SI using 7,742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2,955). Approximately 6.1 million SNPs were subjected to association analysis, and SI-associated variants were identified. We further conducted meta-analysis of Taiwan Biobank significant SNPs with a Korean population-based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein-protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single-nucleotide polymorphisms (SNPs) within three loci, 7q31.31, 17p13.3 and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank eBMD GWAS, and these three cytobands were replicated successfully after meta-analysis with Korean population cohort as well. However, two SNPs were not replicated. Further studies in larger East Asian populations are needed. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI-associated SNPs as well as two novel SI-related genes. Overall, these results provided further insight into the genetic architecture of osteoporosis. This article is protected by copyright. All rights reserved.

AB - The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of bone-mineral density and may be used to predict risk of osteoporotic fracture. We conducted a genome-wide association study (GWAS) for SI using 7,742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2,955). Approximately 6.1 million SNPs were subjected to association analysis, and SI-associated variants were identified. We further conducted meta-analysis of Taiwan Biobank significant SNPs with a Korean population-based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein-protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single-nucleotide polymorphisms (SNPs) within three loci, 7q31.31, 17p13.3 and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank eBMD GWAS, and these three cytobands were replicated successfully after meta-analysis with Korean population cohort as well. However, two SNPs were not replicated. Further studies in larger East Asian populations are needed. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI-associated SNPs as well as two novel SI-related genes. Overall, these results provided further insight into the genetic architecture of osteoporosis. This article is protected by copyright. All rights reserved.

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