title: Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures.
abstract: Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the PTCH1 gene, represented by rs28377268 (freq. 11.4-22.6%) that associates with reduced spine BMD (P=1.0 × 10(-11), β=-0.09). We also identified a new spine BMD signal in RSPO3, rs577721086 (freq. 6.8%), that associates with increased spine BMD (P=6.6 × 10(-10), β=0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the PTCH1 and RSPO3 genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the AXIN1 and SOST loci and a new lead SNP at the EN1 locus.
authors.affiliation: deCODE genetics/Amgen, 101 Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Styrkarsdottir
authors.affiliation: deCODE genetics/Amgen, 101 Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: deCODE genetics/Amgen, 101 Reykjavik, Iceland.
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.affiliation: deCODE genetics/Amgen, 101 Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: Osteoporosis and Bone Biology, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|School of Medicine Sydney, University of Notre Dame Australia, Sydney, New South Wales 2010, Australia.|Clinical School, St Vincent's Hospital, Sydney, New South Wales 2010, Australia.|Faculty of Medicine, University of New South Wales (UNSW), Sydney, New South Wales 2010, Australia.
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Center
authors.affiliation: Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 138-736 Seoul, South Korea.
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Osteoporosis and Bone Biology, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|Faculty of Medicine, University of New South Wales (UNSW), Sydney, New South Wales 2010, Australia.|Centre for Health Technologies, University of Technology, Sydney, New South Wales 2010, Australia.
authors.forename: Tuan V
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Timothy C Y
authors.initials: TCY
authors.lastname: Kwok
authors.affiliation: Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jenny S W
authors.initials: JSW
authors.lastname: Lee
authors.affiliation: JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Ho
authors.affiliation: Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jean
authors.initials: J
authors.lastname: Woo
authors.affiliation: Jockey Club Centre for Osteoporosis Care and Control, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ping-C
authors.initials: PC
authors.lastname: Leung
authors.affiliation: Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 138-736 Seoul, South Korea.
authors.forename: Beom-Jun
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: deCODE genetics/Amgen, 101 Reykjavik, Iceland.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, 6500 HB Nijmegen, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: Department of Orthopedic Surgery, Akureyri Hospital, 603 Akureyri, Iceland.|Institution of Health Science, University of Akureyri, 603 Akureyri, Iceland.
authors.forename: Thorvaldur
authors.initials: T
authors.lastname: Ingvarsson
authors.affiliation: Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 138-736 Seoul, South Korea.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Koh
authors.affiliation: Department of Chemical Pathology, and Laboratory for Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Nelson L S
authors.initials: NLS
authors.lastname: Tang
authors.affiliation: Osteoporosis and Bone Biology, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|School of Medicine Sydney, University of Notre Dame Australia, Sydney, New South Wales 2010, Australia.|Clinical School, St Vincent's Hospital, Sydney, New South Wales 2010, Australia.|Faculty of Medicine, University of New South Wales (UNSW), Sydney, New South Wales 2010, Australia.|Clinical Translation and Advanced Education, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Eisman
authors.affiliation: Nordic Bioscience A/S, 2730 Herlev, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.affiliation: Department of Endocrinology and Metabolism, Landspitali, The National University Hospital of Iceland, 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sigurdsson
authors.affiliation: deCODE genetics/Amgen, 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE genetics/Amgen, 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, 101 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*; D005260:Female; D005598:Fractures, Spontaneous / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007055:Iceland; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000150:complications*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013131:Spine / Q000502:physiology*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D000098907:R-Spondins
chemical_list: D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D019699:Thrombospondins; C000606236:PTCH1 protein, human; C475438:RSPO3 protein, human; D000098907:R-Spondins