Two Rare Mutations in the COL1A2 Gene Associate With Low Bone Mineral Density and Fractures in Iceland.

• Published in: Journal of Bone and Mineral Research
• Main Authors: Styrkarsdottir, Unnur, Thorleifsson, Gudmar, Eiriksdottir, Berglind, Gudjonsson, Sigurjon A, Ingvarsson, Thorvaldur, Center, Jacqueline R, Nguyen, Tuan V, Eisman, John A, Christiansen, Claus, Thorsteinsdottir, Unnur, Sigurdsson, Gunnar, Stefansson, Kari
• Other Authors: 1 DeCODE Genet Amgen, IS-101 Reykjavik, Iceland 2 Res Serv Ctr, Reykjavik, Iceland 3 Akureyri Hosp, Dept Orthoped Surg, Akureyri, Iceland 4 Univ Iceland, Fac Med, Reykjavik, Iceland 5 Garvan Inst Med Res, Sydney, NSW, Australia 6 St Vincents Hosp, Sydney, NSW 2010, Australia 7 Univ New S Wales, Sydney, NSW, Australia 8 Univ Notre Dame Australia, Sydney, NSW, Australia 9 Nord Biosci AS, Herlev, Denmark 10 Natl Univ Hosp Iceland, Landspitali, Dept Endocrinol & Metab, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley-Blackwell 2016
• Subjects: Beinþynning; Arfgengi; END12; Collagen; Genetic Research; Demography; Bone Density; Iceland; Osteoporosis; Osteoporotic Fractures
• Online Access: http://hdl.handle.net/2336/605746; https://doi.org/10.1002/jbmr.2604

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We conducted a genome-wide association study of low bone mineral density (BMD) at the hip and spine utilizing sequence variants found through whole-genome sequencing of 2636 Icelanders. We found two rare missense mutations, p.Gly496Ala and p.Gly703Ser, in the COL1A2 gene that associate with measures of osteoporosis in Icelanders. Mutations in COL1A2 are known to cause the autosomal dominant disorder osteogenesis imperfecta. Both variants associate with low BMD and with osteoporotic fractures. p.Gly496Ala (frequency of 0.105%) shows the strongest association with low BMD at the spine (p = 1.8 × 10(-7) , odds ratio [OR] = 4.61 [95% confidence interval (CI) 2.59, 8.18]), whereas p.Gly703Ser (frequency of 0.050%) is most strongly associated with low BMD at the hip (p = 1.9 × 10(-8) , OR = 9.34 [95% CI 4.28, 20.3]). Association with fractures was p = 2.2 × 10(-5) , OR = 3.75 (95% CI 2.03, 6.93) and p = 0.0023, OR = 4.32 (95% CI 1.69, 11.1), respectively. The carriers of these variants do not have signs of osteogenesis imperfecta other than low BMD, demonstrating that similar mutations in COL1A2 can affect skeletal phenotypes in more than one way. © 2015 American Society for Bone and Mineral Research.