title: Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.
abstract: Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.
authors.affiliation: University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.forename: Patrick
authors.initials: P
authors.lastname: Danoy
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.forename: Eugene
authors.initials: E
authors.lastname: McCloskey
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Nicholson
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
authors.forename: Richard L
authors.initials: RL
authors.lastname: Prince
authors.forename: John A
authors.initials: JA
authors.lastname: Eisman
authors.forename: Graeme
authors.initials: G
authors.lastname: Jones
authors.forename: Philip N
authors.initials: PN
authors.lastname: Sambrook
authors.forename: Ian R
authors.initials: IR
authors.lastname: Reid
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Dennison
authors.forename: John
authors.initials: J
authors.lastname: Wark
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Chris
authors.initials: C
authors.lastname: Esapa
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cox
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Addison
authors.forename: Linda A
authors.initials: LA
authors.lastname: Bradbury
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Center
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.forename: Catherine
authors.initials: C
authors.lastname: Cremin
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.forename: Dieter
authors.initials: D
authors.lastname: Felsenberg
authors.forename: Claus-C
authors.initials: CC
authors.lastname: Glüer
authors.forename: Johanna
authors.initials: J
authors.lastname: Hadler
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Henry
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kotowicz
authors.forename: Joanna
authors.initials: J
authors.lastname: Makovey
authors.forename: Sing C
authors.initials: SC
authors.lastname: Nguyen
authors.forename: Tuan V
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Julie A
authors.initials: JA
authors.lastname: Pasco
authors.forename: Karena
authors.initials: K
authors.lastname: Pryce
authors.forename: David M
authors.initials: DM
authors.lastname: Reid
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Christian
authors.initials: C
authors.lastname: Roux
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Unnur
authors.initials: U
authors.lastname: Styrkarsdottir
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Rumbidzai
authors.initials: R
authors.lastname: Tichawangana
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015519:Bone Density; D016022:Case-Control Studies; D018118:Chloride Channels / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D050723:Fractures, Bone / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D058574:Integrin-Binding Sialoprotein / Q000235:genetics; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D023421:Models, Animal; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D015663:Osteoporosis, Postmenopausal / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011509:Proteoglycans / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D055751:SOXC Transcription Factors / Q000235:genetics; D019699:Thrombospondins / Q000235:genetics*; D000097763:Polypeptide N-acetylgalactosaminyltransferase; D000098907:R-Spondins
chemical_list: D018118:Chloride Channels; D058574:Integrin-Binding Sialoprotein; D053779:Latent TGF-beta Binding Proteins; D017350:N-Acetylgalactosaminyltransferases; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D055751:SOXC Transcription Factors; D019699:Thrombospondins; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C097540:CLCN7 protein, human; C546871:IBSP protein, human; C509038:LTBP3 protein, human; C475438:RSPO3 protein, human; D000098907:R-Spondins; C083431:SOX4 protein, human; C071736:betaglycan