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

ABSTRACT 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...

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Bibliographic Details
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: Icelandic deCODE study, the Danish PERF study
Format: Article in Journal/Newspaper
Language:English
Published: Oxford University Press (OUP) 2015
Subjects:
Orthopedics and Sports Medicine
Endocrinology, Diabetes and Metabolism
Iceland
Online Access:http://dx.doi.org/10.1002/jbmr.2604
https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fjbmr.2604
https://academic.oup.com/jbmr/article-pdf/31/1/173/56652708/jbmr2604.pdf
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Summary:ABSTRACT 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.

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