{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T19:47:14Z","timestamp":1767901634326,"version":"3.49.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T00:00:00Z","timestamp":1709596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007225","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>The purpose of this study was to identify new independent significant SNPs associated with osteoporosis using data from the Taiwan Biobank (TWBB).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Material and Methods<\/jats:title>\n                  <jats:p>The dataset was divided into discovery (60%) and replication (40%) subsets. Following data quality control, genome-wide association study (GWAS) analysis was performed, adjusting for sex, age, and the top 5 principal components, employing the Scalable and Accurate Implementation of the Generalized mixed model approach. This was followed by a meta-analysis of TWBB1 and TWBB2. The Functional Mapping and Annotation (FUMA) platform was used to identify osteoporosis-associated loci. Manhattan and quantile\u2013quantile plots were generated using the FUMA platform to visualize the results. Independent significant SNPs were selected based on genome-wide significance (P\u2009&amp;lt;\u20095\u2009\u00d7\u200910\u22128) and independence from each other (r2\u2009&amp;lt;\u20090.6) within a 1\u00a0Mb window. Positional, eQTL(expression quantitative trait locus), and Chromatin interaction mapping were used to map SNPs to genes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A total of 29\u2009084 individuals (3154 osteoporosis cases and 25\u2009930 controls) were used for GWAS analysis (TWBB1 data), and 18\u2009918 individuals (1917 cases and 17\u2009001 controls) were utilized for replication studies (TWBB2 data). We identified a new independent significant SNP for osteoporosis in TWBB1, with the lead SNP rs76140829 (minor allele frequency\u2009=\u20090.055, P-value\u2009=\u20091.15\u2009\u00d7\u200910\u221208). Replication of the association was performed in TWBB2, yielding a P-value of 6.56\u2009\u00d7\u200910\u22123. The meta-analysis of TWBB1 and TWBB2 data demonstrated a highly significant association for SNP rs76140829 (P-value\u2009=\u20097.52\u2009\u00d7\u200910\u221210). In the positional mapping of rs76140829, 6 genes (HABP2, RP11-481H12.1, RNU7-165P, RP11-139\u00a0K1.2, RP11-57H14.3, and RP11-214\u00a0N15.5) were identified through chromatin interaction mapping in mesenchymal stem cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our GWAS analysis using the Taiwan Biobank dataset unveils rs76140829 in the VTI1A gene as a key risk variant associated with osteoporosis. This finding expands our understanding of the genetic basis of osteoporosis and highlights the potential regulatory role of this SNP in mesenchymal stem cells.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jbmrpl\/ziae028","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T23:33:50Z","timestamp":1709681630000},"source":"Crossref","is-referenced-by-count":3,"title":["Identification of an novel genetic variant associated with osteoporosis: insights from the Taiwan Biobank Study"],"prefix":"10.1093","volume":"8","author":[{"given":"Yi-Ching","family":"Liaw","sequence":"first","affiliation":[{"name":"The University of Tokyo Department of Computational Biology and Medical Sciences, Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, , Tokyo 108-8639, Japan"},{"name":"Chung Shan Medical University Department of Public Health and Institute of Public Health, , Taichung 40201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Matsuda","sequence":"additional","affiliation":[{"name":"The University of Tokyo Department of Computational Biology and Medical Sciences, Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, , Tokyo 108-8639, Japan"},{"name":"Human Genome Center, Institute of Medical Science, The University of Tokyo, Laboratory of Genome Technology, Tokyo 108-8639, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung-Po","family":"Liaw","sequence":"additional","affiliation":[{"name":"Chung Shan Medical University Department of Public Health and Institute of Public Health, , Taichung 40201, Taiwan"},{"name":"Institute of Medicine, Chung Shan Medical University , Taichung 40201, Taiwan"},{"name":"Chung Shan Medical University Hospital Department of Medical Imaging, , Taichung 40201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,3,5]]},"reference":[{"issue":"12","key":"2024042315335941700_ref1","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1007\/s00198-006-0172-4","article-title":"An estimate of the worldwide prevalence and disability associated with osteoporotic fractures","volume":"17","author":"Johnell","year":"2006","journal-title":"Osteoporos Int"},{"issue":"4","key":"2024042315335941700_ref2","doi-asserted-by":"crossref","first-page":"750","DOI":"10.5534\/wjmh.200099","article-title":"Gender differences in osteoporosis: a single-center observational study","volume":"39","author":"De Martinis","year":"2021","journal-title":"World J Mens Health"},{"issue":"5","key":"2024042315335941700_ref3","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.tem.2016.03.006","article-title":"Osteoporosis and bone mass disorders: from gene pathways to treatments","volume":"27","author":"Rivadeneira","year":"2016","journal-title":"Trends Endocrinol Metab"},{"issue":"9321","key":"2024042315335941700_ref4","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1016\/S0140-6736(02)08761-5","article-title":"Diagnosis of osteoporosis and assessment of fracture risk","volume":"359","author":"Kanis","year":"2002","journal-title":"Lancet"},{"issue":"2","key":"2024042315335941700_ref5","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1359\/jbmr.060806","article-title":"Meta-analysis of genome-wide scans provides evidence for sex-and site-specific regulation of bone mass","volume":"22","author":"Ioannidis","year":"2007","journal-title":"J Bone Miner Res"},{"issue":"4","key":"2024042315335941700_ref6","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1002\/jbmr.5650110414","article-title":"The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins","volume":"11","author":"Arden","year":"1996","journal-title":"J Bone Miner Res"},{"issue":"3","key":"2024042315335941700_ref7","first-page":"231","article-title":"The genetics of osteoporosis","volume":"32","author":"Williams","year":"2007","journal-title":"Acta Reumatol Port"},{"issue":"6","key":"2024042315335941700_ref8","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3109\/13697137.2012.656160","article-title":"Estrogen-related genes and postmenopausal osteoporosis risk","volume":"15","author":"Mendoza","year":"2012","journal-title":"Climacteric"},{"issue":"8","key":"2024042315335941700_ref9","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1359\/jbmr.1998.13.8.1318","article-title":"Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: a twin study","volume":"13","author":"Howard","year":"1998","journal-title":"J Bone Miner Res"},{"issue":"10","key":"2024042315335941700_ref10","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1038\/ng.3949","article-title":"Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis","volume":"49","author":"Kemp","year":"2017","journal-title":"Nat Genet"},{"issue":"2","key":"2024042315335941700_ref11","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41588-018-0302-x","article-title":"An atlas of genetic influences on osteoporosis in humans and mice","volume":"51","author":"Morris","year":"2019","journal-title":"Nat Genet"},{"issue":"1","key":"2024042315335941700_ref12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ajhg.2017.06.005","article-title":"10 years of GWAS discovery: biology, function, and translation","volume":"101","author":"Visscher","year":"2017","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2024042315335941700_ref13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s42003-018-0261-x","article-title":"A scientometric review of genome-wide association studies","volume":"2","author":"Mills","year":"2019","journal-title":"Commun Biol"},{"issue":"3","key":"2024042315335941700_ref14","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.ajhg.2009.01.025","article-title":"Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups","volume":"84","author":"Xiong","year":"2009","journal-title":"Am J Hum Genet"},{"issue":"7571","key":"2024042315335941700_ref15","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nature14878","article-title":"Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture","volume":"526","author":"Zheng","year":"2015","journal-title":"Nature"},{"issue":"11","key":"2024042315335941700_ref16","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1038\/ng.446","article-title":"Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies","volume":"41","author":"Rivadeneira","year":"2009","journal-title":"Nat Genet"},{"issue":"5","key":"2024042315335941700_ref17","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.2249","article-title":"Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture","volume":"44","author":"Estrada","year":"2012","journal-title":"Nat Genet"},{"issue":"11","key":"2024042315335941700_ref18","doi-asserted-by":"crossref","first-page":"3054","DOI":"10.1093\/hmg\/ddt675","article-title":"Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS\/GENOMOS consortium","volume":"23","author":"Moayyeri","year":"2014","journal-title":"Hum Mol Genet"},{"issue":"1","key":"2024042315335941700_ref19","first-page":"1","article-title":"Vitamin D receptor (VDR) gene FokI, BsmI, ApaI, and TaqI polymorphisms and osteoporosis risk: a meta-analysis","volume":"21","author":"Yadav","year":"2020","journal-title":"EJMHG"},{"issue":"2","key":"2024042315335941700_ref20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.repbre.2021.05.001","article-title":"Genome-wide association analysis reveals genetic variations and candidate genes associated with growth-related traits and condition factor in Takifugu bimaculatus","volume":"1","author":"Zhou","year":"2021","journal-title":"Reprod Breed"},{"issue":"3","key":"2024042315335941700_ref21","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.clnu.2022.01.020","article-title":"Effect of dietary calcium on the gender-specific association between polymorphisms in the PTPRD locus and osteoporosis","volume":"41","author":"Bae","year":"2022","journal-title":"Clin Nutr"},{"issue":"1","key":"2024042315335941700_ref22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.tig.2018.10.004","article-title":"Dissecting the genetics of osteoporosis using systems approaches","volume":"35","author":"Al-Barghouthi","year":"2019","journal-title":"Trends Genet"},{"issue":"5","key":"2024042315335941700_ref23","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1210\/er.2009-0044","article-title":"Genetics of osteoporosis","volume":"31","author":"Ralston","year":"2010","journal-title":"Endocr Rev"},{"issue":"1","key":"2024042315335941700_ref24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41413-021-00143-3","article-title":"Twelve years of GWAS discoveries for osteoporosis and related traits: advances, challenges and applications","volume":"9","author":"Zhu","year":"2021","journal-title":"Bone Res"},{"issue":"7539","key":"2024042315335941700_ref25","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature14248","article-title":"Integrative analysis of 111 reference human epigenomes","volume":"518","author":"Roadmap","year":"2015","journal-title":"Nature"},{"issue":"7414","key":"2024042315335941700_ref26","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"Consortium EP","year":"2012","journal-title":"Nature"},{"issue":"8","key":"2024042315335941700_ref27","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1016\/j.celrep.2016.10.061","article-title":"A compendium of chromatin contact maps reveals spatially active regions in the human genome","volume":"17","author":"Schmitt","year":"2016","journal-title":"Cell Rep"},{"issue":"3","key":"2024042315335941700_ref28","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am J Hum Genet"},{"issue":"9","key":"2024042315335941700_ref29","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","article-title":"Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies","volume":"50","author":"Zhou","year":"2018","journal-title":"Nat Genet"},{"issue":"1","key":"2024042315335941700_ref30","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat Commun"},{"issue":"9","key":"2024042315335941700_ref31","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1101\/gr.137323.112","article-title":"Annotation of functional variation in personal genomes using RegulomeDB","volume":"22","author":"Boyle","year":"2012","journal-title":"Genome Res"},{"issue":"3","key":"2024042315335941700_ref32","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A EnAn itwork for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat Genet"},{"issue":"7539","key":"2024042315335941700_ref33","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature14248","article-title":"53 SpmCLH, 8 PiBBECJFEJRHMMAMARB. Integrative analysis of 111 reference human epigenomes","volume":"518","author":"5 RECIacKAMWEJBM","year":"2015","journal-title":"Nature"},{"issue":"3","key":"2024042315335941700_ref34","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nmeth.1906","article-title":"ChromHMM: automating chromatin-state discovery and characterization","volume":"9","author":"Ernst","year":"2012","journal-title":"Nat Methods"},{"issue":"16","key":"2024042315335941700_ref35","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: thenotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"2024042315335941700_ref36","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/ejhg.2011.39","article-title":"Genomic inflation factors under polygenic inheritance","volume":"19","author":"Yang","year":"2011","journal-title":"Eur J Hum Genet"},{"issue":"4","key":"2024042315335941700_ref37","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/gepi.20303","article-title":"Estimation of the multiple testing burden for genomewide association studies of nearly all common variants","volume":"32","author":"Pe'er","year":"2008","journal-title":"Genet Epidemiol"},{"issue":"8","key":"2024042315335941700_ref38","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/ejhg.2015.269","article-title":"The (in) famous GWAS P-value threshold revisited and updated for low-frequency variants","volume":"24","author":"Fadista","year":"2016","journal-title":"Eur J Hum Genet"},{"issue":"6235","key":"2024042315335941700_ref39","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1126\/science.1262110","article-title":"The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans","volume":"348","author":"Consortium G","year":"2015","journal-title":"Science"},{"issue":"10","key":"2024042315335941700_ref40","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1038\/ng.2756","article-title":"Systematic identification of trans eQTLs as putative drivers of known disease associations","volume":"45","author":"Westra","year":"2013","journal-title":"Nat Genet"},{"issue":"1","key":"2024042315335941700_ref41","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/ng.3737","article-title":"Identification of context-dependent expression quantitative trait loci in whole blood","volume":"49","author":"Zhernakova","year":"2017","journal-title":"Nat Genet"},{"issue":"10","key":"2024042315335941700_ref42","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1038\/nn.3801","article-title":"Genetic variability in the regulation of gene expression in ten regions of the human brain","volume":"17","author":"Ramasamy","year":"2014","journal-title":"Nat Neurosci"},{"key":"2024042315335941700_ref43","author":"NCBI","year":"2022"},{"issue":"D1","key":"2024042315335941700_ref44","doi-asserted-by":"crossref","first-page":"D1408","DOI":"10.1093\/nar\/gkab853","article-title":"VannoPortal: multiscale functional annotation of human genetic variants for interrogating molecular mechanism of traits and diseases","volume":"50","author":"Huang","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"18","key":"2024042315335941700_ref45","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1093\/bioinformatics\/btab122","article-title":"PICS2: next-generation fine mapping via probabilistic identification of causal SNPs","volume":"37","author":"Taylor","year":"2021","journal-title":"Bioinformatics"},{"issue":"6","key":"2024042315335941700_ref46","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/ng.3286","article-title":"Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C","volume":"47","author":"Mifsud","year":"2015","journal-title":"Nat Genet"},{"issue":"1","key":"2024042315335941700_ref47","doi-asserted-by":"crossref","first-page":"10069","DOI":"10.1038\/ncomms10069","article-title":"Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci","volume":"6","author":"Martin","year":"2015","journal-title":"Nat Commun"},{"issue":"1","key":"2024042315335941700_ref48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-016-1078-x","article-title":"Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23","volume":"17","author":"McGovern","year":"2016","journal-title":"Genome Biol"},{"issue":"5","key":"2024042315335941700_ref49","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/j.cell.2016.09.037","article-title":"Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters","volume":"167","author":"Javierre","year":"2016","journal-title":"Cell"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmrplus\/advance-article-pdf\/doi\/10.1093\/jbmrpl\/ziae028\/56864990\/ziae028.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/8\/5\/ziae028\/57308057\/ziae028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/8\/5\/ziae028\/57308057\/ziae028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T15:34:33Z","timestamp":1713886473000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/doi\/10.1093\/jbmrpl\/ziae028\/7621152"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,5]]},"references-count":49,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,3,28]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmrpl\/ziae028","relation":{},"ISSN":["2473-4039"],"issn-type":[{"value":"2473-4039","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,5,1]]},"published":{"date-parts":[[2024,3,5]]},"article-number":"ziae028"}}