title: 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 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.
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Styrkarsdottir
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: Research Service Center, Reykjavik, Iceland.
authors.forename: Berglind
authors.initials: B
authors.lastname: Eiriksdottir
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.affiliation: Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Thorvaldur
authors.initials: T
authors.lastname: Ingvarsson
authors.affiliation: Garvan Institute of Medical Research, Sydney, Australia.|St. Vincent's Hospital, Sydney, Australia.|University of New South Wales (UNSW), Sydney, Australia.
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Center
authors.affiliation: Garvan Institute of Medical Research, Sydney, Australia.|University of New South Wales (UNSW), Sydney, Australia.
authors.forename: Tuan V
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Garvan Institute of Medical Research, Sydney, Australia.|St. Vincent's Hospital, Sydney, Australia.|University of New South Wales (UNSW), Sydney, Australia.|University of Notre Dame Australia (UNDA), Sydney, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Eisman
authors.affiliation: Nordic Bioscience A/S, Herlev, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Endocrinology and Metabolism, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sigurdsson
authors.affiliation: deCODE genetics/Amgen, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics*; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D007055:Iceland / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I
keywords: COLLAGEN; GENETIC RESEARCH; HUMAN ASSOCIATION STUDIES; STATISTICAL METHODS