{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:16:42Z","timestamp":1792603002638,"version":"4.5.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,1,28]],"date-time":"2019-01-28T00:00:00Z","timestamp":1548633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2019,2,28]],"date-time":"2019-02-28T00:00:00Z","timestamp":1551312000000},"content-version":"vor","delay-in-days":31,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31571291"],"award-info":[{"award-number":["31571291"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31771417"],"award-info":[{"award-number":["31771417"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31501026"],"award-info":[{"award-number":["31501026"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81460223"],"award-info":[{"award-number":["81460223"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,6,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Bone mineral density (BMD) at various skeletal sites have shared genetic determinants. In the present study, aiming to identify shared loci associated with BMD, we conducted a joint association study of a genomewide association study (GWAS) and a meta-analysis of BMD at different skeletal sites: (i) a single GWAS of heel BMD in 142,487 individuals from the UK Biobank, and (ii) a meta-analysis of 30 GWASs of total body (TB) BMD in 66,628 individuals from the Genetic Factors for Osteoporosis (GEFOS) Consortium. The genetic correlation coefficient of the two traits was estimated to be 0.57. We performed joint association analysis with a recently developed statistical method multi-trait analysis of GWAS (MTAG) to account for trait heterogeneity and sample overlap. The joint association analysis combining samples of up to 209,115 individuals identified 18 novel loci associated with BMD at the genomewide significance level (\u03b1\u2009=\u20095.0\u2009\u00d7\u200910\u20138), explaining an additional 0.43% and 0.60% of heel-BMD and TB-BMD heritability, respectively. The vast majority of the identified lead SNPs or their proxies exerted local expression quantitative trait loci (cis-eQTL) activity. Credible risk variants, defined as those SNPs located within 500 kilobases (kb) of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in transcription factor binding sites (p\u2009=\u20093.58\u2009\u00d7\u200910\u20134) and coding regions (p\u2009=\u20095.71\u2009\u00d7\u200910\u20134). Fifty-six candidate genes were prioritized at these novel loci using multiple sources of information, including several genes being previously reported to play a role in bone biology but not reported in previous GWASs (PPARG, FBN2, DEF6, TNFRSF19, and NFE2L1). One newly identified gene, SCMH1, was shown to upregulate the expression of several bone biomarkers, including alkaline phosphatase (ALP), collagen type 1 (COL-I), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), in mouse osteoblastic MC3T3-E1 cells, highlighting its regulatory role in bone formation. Our results may provide useful candidate genes for future functional investigations. \u00a9 2019 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3681","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T03:14:20Z","timestamp":1548731660000},"page":"1086-1094","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Joint Association Analysis Identified 18 New Loci for Bone Mineral Density"],"prefix":"10.1093","volume":"34","author":[{"given":"Yu-Fang","family":"Pei","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health Medical College of Soochow University Jiangsu China"},{"name":"Department of Epidemiology and Health Statistics, School of Public Health Medical College of Soochow University Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health Medical College of Soochow University Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health Medical College of Soochow University Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao-Le","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Circadian Clock, School of Biology & Basic Medical Sciences Medical College of Soochow University Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health Medical College of Soochow University Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health Medical College of Soochow University Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health Medical College of Soochow University Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health Medical College of Soochow University Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Tong","family":"Wei","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health Medical College of Soochow University Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health Medical College of Soochow University Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui-Juan","family":"Feng","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health Medical College of Soochow University Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health Medical College of Soochow University Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Hai","sequence":"additional","affiliation":[{"name":"Inner Mongolia Autonomous Region People's Hospital Hohhot Inner Mongolia China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Ran","sequence":"additional","affiliation":[{"name":"School of Medical Instrument and Food Engineering University of Shanghai for Science and Technology Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology and Genomics, School of Public Health Medical College of Soochow University Jiangsu China"},{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health Medical College of Soochow University Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,1,28]]},"reference":[{"issue":"4","key":"2024021014430792400_jbmr3681-bib-0001","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/S0015-0282(16)55848-8","article-title":"Osteoporosis: screening, prevention, and management","volume":"59","author":"Notelovitz","year":"1993","journal-title":"Fertil Steril"},{"issue":"3","key":"2024021014430792400_jbmr3681-bib-0002","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1359\/jbmr.061113","article-title":"Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025","volume":"22","author":"Burge","year":"2007","journal-title":"J Bone Miner Res"},{"issue":"3","key":"2024021014430792400_jbmr3681-bib-0003","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1210\/edrv.23.3.0464","article-title":"Genetics of osteoporosis","volume":"23","author":"Peacock","year":"2002","journal-title":"Endocr Rev"},{"issue":"5","key":"2024021014430792400_jbmr3681-bib-0004","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":"1","key":"2024021014430792400_jbmr3681-bib-0005","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ajhg.2017.12.005","article-title":"Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects","volume":"102","author":"Medina-Gomez","year":"2018","journal-title":"Am J Hum Genet"},{"issue":"10","key":"2024021014430792400_jbmr3681-bib-0006","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":"7571","key":"2024021014430792400_jbmr3681-bib-0007","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":"3","key":"2024021014430792400_jbmr3681-bib-0008","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD Score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"issue":"11","key":"2024021014430792400_jbmr3681-bib-0009","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ng.3406","article-title":"An atlas of genetic correlations across human diseases and traits","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"issue":"2","key":"2024021014430792400_jbmr3681-bib-0010","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41588-017-0009-4","article-title":"Multi-trait analysis of genome-wide association summary statistics using MTAG","volume":"50","author":"Turley","year":"2018","journal-title":"Nat Genet"},{"issue":"3","key":"2024021014430792400_jbmr3681-bib-0011","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/77100","article-title":"Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28","volume":"25","author":"Taillon-Miller","year":"2000","journal-title":"Nat Genet"},{"issue":"7678","key":"2024021014430792400_jbmr3681-bib-0012","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature24284","article-title":"Association analysis identifies 65 new breast cancer risk loci","volume":"551","author":"Michailidou","year":"2017","journal-title":"Nature"},{"issue":"10","key":"2024021014430792400_jbmr3681-bib-0013","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1038\/ng.3955","article-title":"A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci","volume":"49","author":"Chang","year":"2017","journal-title":"Nat Genet"},{"issue":"12","key":"2024021014430792400_jbmr3681-bib-0014","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1038\/ng.3785","article-title":"Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer","volume":"49","author":"Milne","year":"2017","journal-title":"Nat Genet"},{"issue":"11","key":"2024021014430792400_jbmr3681-bib-0015","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1038\/ng.3404","article-title":"Partitioning heritability by functional annotation using genome-wide association summary statistics","volume":"47","author":"Finucane","year":"2015","journal-title":"Nat Genet"},{"issue":"5","key":"2024021014430792400_jbmr3681-bib-0016","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/gepi.20504","article-title":"Evaluating the power to discriminate between highly correlated SNPs in genetic association studies","volume":"34","author":"Udler","year":"2010","journal-title":"Genet Epidemiol"},{"issue":"6","key":"2024021014430792400_jbmr3681-bib-0017","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The GTEx Consortium. The Genotype-Tissue Expression (GTEx) project","volume":"45","year":"2013","journal-title":"Nat Genet"},{"key":"2024021014430792400_jbmr3681-bib-0018","doi-asserted-by":"crossref","first-page":"5890","DOI":"10.1038\/ncomms6890","article-title":"Biological interpretation of genome-wide association studies using predicted gene functions","volume":"6","author":"Pers","year":"2015","journal-title":"Nat Commun"},{"issue":"5","key":"2024021014430792400_jbmr3681-bib-0019","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat Genet"},{"issue":"10","key":"2024021014430792400_jbmr3681-bib-0020","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":"7621","key":"2024021014430792400_jbmr3681-bib-0021","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/nature19356","article-title":"High-throughput discovery of novel developmental phenotypes","volume":"537","author":"Dickinson","year":"2016","journal-title":"Nature"},{"issue":"6","key":"2024021014430792400_jbmr3681-bib-0022","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1083\/jcb.201003089","article-title":"Fibrillin-1 and -2 differentially modulate endogenous TGF-beta and BMP bioavailability during bone formation","volume":"190","author":"Nistala","year":"2010","journal-title":"J Cell Biol"},{"issue":"4","key":"2024021014430792400_jbmr3681-bib-0023","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s00774-005-0599-2","article-title":"Distinct effects of PPARgamma insufficiency on bone marrow cells, osteoblasts, and osteoclastic cells","volume":"23","author":"Kawaguchi","year":"2005","journal-title":"J Bone Miner Metab"},{"issue":"44","key":"2024021014430792400_jbmr3681-bib-0024","doi-asserted-by":"crossref","first-page":"34126","DOI":"10.1074\/jbc.M110.125328","article-title":"Extracellular microfibrils control osteoblast-supported osteoclastogenesis by restricting TGF{beta} stimulation of RANKL production","volume":"285","author":"Nistala","year":"2010","journal-title":"J Biol Chem"},{"issue":"3","key":"2024021014430792400_jbmr3681-bib-0025","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1007\/s10059-013-0159-x","article-title":"SLAT negatively regulates RANKL-induced osteoclast differentiation","volume":"36","author":"Youn","year":"2013","journal-title":"Mol Cells"},{"issue":"9","key":"2024021014430792400_jbmr3681-bib-0026","doi-asserted-by":"crossref","first-page":"3436","DOI":"10.4049\/jimmunol.1601716","article-title":"Def6 restrains osteoclastogenesis and inflammatory bone resorption","volume":"198","author":"Binder","year":"2017","journal-title":"J Immunol"},{"issue":"19","key":"2024021014430792400_jbmr3681-bib-0027","doi-asserted-by":"crossref","first-page":"14438","DOI":"10.1074\/jbc.M109.052001","article-title":"Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) regulates differentiation fate of human mesenchymal (stromal) stem cells through canonical Wnt signaling and C\/EBP","volume":"285","author":"Qiu","year":"2010","journal-title":"J Biol Chem"},{"issue":"2","key":"2024021014430792400_jbmr3681-bib-0028","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1152\/physiolgenomics.00105.2009","article-title":"Targeted disruption of nuclear factor erythroid-derived 2-like 1 in osteoblasts reduces bone size and bone formation in mice","volume":"40","author":"Kim","year":"2010","journal-title":"Physiol Genomics"},{"issue":"3","key":"2024021014430792400_jbmr3681-bib-0029","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1242\/dev.02747","article-title":"Mammalian Polycomb Scmh1 mediates exclusion of Polycomb complexes from the XY body in the pachytene spermatocytes","volume":"134","author":"Takada","year":"2007","journal-title":"Development"},{"issue":"2","key":"2024021014430792400_jbmr3681-bib-0030","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s003350010240","article-title":"Cloning, expression, genomic localization, and enzymatic activities of the mouse homolog of prostate-specific membrane antigen\/NAALADase\/folate hydrolase","volume":"12","author":"Bacich","year":"2001","journal-title":"Mamm Genome"},{"issue":"21","key":"2024021014430792400_jbmr3681-bib-0031","doi-asserted-by":"crossref","first-page":"12404","DOI":"10.1073\/pnas.95.21.12404","article-title":"The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations","volume":"95","author":"Flores-Rozas","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2024021014430792400_jbmr3681-bib-0032","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/geno.1998.5293","article-title":"Cloning, chromosomal mapping, and regulatory properties of the human type 9 adenylyl cyclase (ADCY9)","volume":"50","author":"Hacker","year":"1998","journal-title":"Genomics"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.3681","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbmr.3681","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbmr.3681","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/34\/6\/1086\/56654460\/jbmr3681.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/34\/6\/1086\/56654460\/jbmr3681.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T15:03:31Z","timestamp":1710342211000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/34\/6\/1086-1094\/7605846"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,28]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,1,28]]},"published-print":{"date-parts":[[2019,6,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.3681","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,6,1]]},"published":{"date-parts":[[2019,1,28]]},"assertion":[{"value":"2018-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}