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However, the genetic etiology of osteoporosis in men is still poorly understood. We aimed to identify the genetic variants and candidate genes associated with extremely low or high BMD for a better understanding of the biology underlying low bone density that may point to potential therapeutic targets for increasing bone mass. Subjects from the Osteoporotic Fractures in Men Study (MrOS) cohort were evaluated by age and BMI\u2010adjusted total hip BMD. Those with BMD values 3 SDs away from the mean were selected and the remaining individuals whose adjusted BMD ranked at the highest or lowest 100 were included. Men with the lowest adjusted BMD (\n                    <jats:italic>N<\/jats:italic>\n                    =\u200998) and highest adjusted BMD (\n                    <jats:italic>N<\/jats:italic>\n                    =\u2009110) were chosen for exome sequencing. Controls (\n                    <jats:italic>N<\/jats:italic>\n                    =\u200982) were men of Northern and Western European descent from the US Utah population of the 1000 Genomes Project. Fisher's exact test was performed to compare low\u2010 or high\u2010BMD subjects with controls for single\u2010gene associations. Additionally, sets of candidate genes causative of heritable disorders of connective tissue, including osteogenesis imperfecta (OI) and Ehlers\u2010Danlos syndrome (EDS), were grouped for multigene and mutation burden analyses. No single\u2010gene associations with rare variants were found for either the low BMD group (33 genes) or high BMD group (18 genes). In the group of OI genes, we detected a significant threefold increased accumulation of rare variants in low\u2010BMD subjects compared with controls (\n                    <jats:italic>p<\/jats:italic>\n                    =\u20090.009). Additionally, genes associated with EDS had a twofold increased frequency in low\u2010BMD subjects compared with controls (\n                    <jats:italic>p<\/jats:italic>\n                    =\u20090.03). These findings reveal a rare variant burden in OI and EDS disease genes at low BMD, which suggests a potential gene\u2010panel approach to screen for multivariant associations in larger cohorts. \u00a9 2019 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10335","type":"journal-article","created":{"date-parts":[[2019,12,20]],"date-time":"2019-12-20T15:44:46Z","timestamp":1576856686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS)"],"prefix":"10.1093","volume":"4","author":[{"given":"Shan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahim","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston TX USA"},{"name":"Osteogenesis Imperfecta Clinic, Kennedy Krieger Institute  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Jhangiani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston TX USA"},{"name":"Human Genome Sequencing Center Baylor College of Medicine  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep C","family":"Akdemir","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9713-7107","authenticated-orcid":false,"given":"Philippe M","family":"Campeau","sequence":"additional","affiliation":[{"name":"University of Montreal Medical Genetics Service  Montr\u00e9al QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F","family":"Klein","sequence":"additional","affiliation":[{"name":"School of Medicine Oregon Health &amp; Science University  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2619-7839","authenticated-orcid":false,"given":"Carrie","family":"Nielson","sequence":"additional","affiliation":[{"name":"School of Medicine Oregon Health &amp; Science University  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0103-876X","authenticated-orcid":false,"given":"Hongzheng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna M","family":"Muzny","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston TX USA"},{"name":"Human Genome Sequencing Center Baylor College of Medicine  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Boerwinkle","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center Baylor College of Medicine  Houston TX USA"},{"name":"Human Genetics Center and Department of Epidemiology UTHealth School of Public Health  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston TX USA"},{"name":"Human Genome Sequencing Center Baylor College of Medicine  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric S","family":"Orwoll","sequence":"additional","affiliation":[{"name":"School of Medicine Oregon Health &amp; 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New mutations old statistical challenges. bioRxiv. 2017;115964."}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbm4.10335","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbm4.10335","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbm4.10335","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbm4.10335","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T09:55:05Z","timestamp":1710410105000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/7512291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,22]]},"references-count":44,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,3]]}},"alternative-id":["10.1002\/jbm4.10335"],"URL":"https:\/\/doi.org\/10.1002\/jbm4.10335","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/JBM4.10335\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10335\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10335\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10335\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10335\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/JBM4.10335\/v2\/decision1","asserted-by":"object"}]},"ISSN":["2473-4039","2473-4039"],"issn-type":[{"value":"2473-4039","type":"print"},{"value":"2473-4039","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,22]]},"assertion":[{"value":"2019-10-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e10335"}}