TY - JOUR
T1 - Meta-Analysis of Genome-Wide Association Studies Identifies Three Loci Associated With Stiffness Index of the Calcaneus
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
N1 - Funding Information:
1School of Pharmacy, Taipei Medical University, Taipei, Taiwan 2Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan 3Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan 4Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan 5Graduate Institute of Injury, Prevention and Control, College of Public Health, Taipei Medical University, Taipei, Taiwan 6Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 7Department of Preventive Medicine, College of Medicine, Hanyang University, Seoul, South Korea 8Institute for Health and Society, Hanyang University, Seoul, South Korea 9Department of Anesthesiology, Taipei Medical University, Taipei, Taiwan 10Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan 11Department of Pharmacy, Taipei Medical University-Wanfang Hospital, Taipei, Taiwan 12Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan 13Department of Medicine Research, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan
Funding Information:
This work was supported by grants from the Ministry of Science and Technology, Taiwan (MOST 105-2628-B-038-001-MY4; MOST 106-2923-B-038-002), the Higher Education Sprout Project by the Ministry of Education in Taiwan (MOE DP2-107-21121-A-05), the Japan Osteoporosis Foundation, and the research program funded by the Korea Centers for Disease Control and Prevention (2017N-E71001-00).
Publisher Copyright:
© 2019 American Society for Bone and Mineral Research
PY - 2019/7
Y1 - 2019/7
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.
KW - GENOME-WIDE ASSOCIATION STUDY
KW - HEEL BONE MINERAL DENSITY
KW - OSTEOPOROSIS
KW - STIFFNESS INDEX
KW - TAIWAN BIOBANK
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U2 - 10.1002/jbmr.3703
DO - 10.1002/jbmr.3703
M3 - Article
C2 - 30779856
SN - 0884-0431
VL - 34
SP - 1275
EP - 1283
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 7
M1 - e3703
ER -
