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J Bone Miner Res. 2016 Jan;31(1):173-9. doi: 10.1002/jbmr.2604. Epub 2015 Aug 29.

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

Author information

1
deCODE genetics/Amgen, Reykjavik, Iceland.
2
Research Service Center, Reykjavik, Iceland.
3
Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland.
4
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
5
Garvan Institute of Medical Research, Sydney, Australia.
6
St. Vincent's Hospital, Sydney, Australia.
7
University of New South Wales (UNSW), Sydney, Australia.
8
University of Notre Dame Australia (UNDA), Sydney, Australia.
9
Nordic Bioscience A/S, Herlev, Denmark.
10
Department of Endocrinology and Metabolism, Landspitali, The National University Hospital of Iceland, Reykjavik, 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 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.

KEYWORDS:

COLLAGEN; GENETIC RESEARCH; HUMAN ASSOCIATION STUDIES; STATISTICAL METHODS

PMID:
26235824
DOI:
10.1002/jbmr.2604
[Indexed for MEDLINE]
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