title: Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.
abstract: Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Alireza
authors.initials: A
authors.lastname: Moayyeri
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Hsu
authors.forename: David
authors.initials: D
authors.lastname: Karasik
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.forename: Su-Mei
authors.initials: SM
authors.lastname: Xiao
authors.forename: Carrie
authors.initials: C
authors.lastname: Nielson
authors.forename: Priya
authors.initials: P
authors.lastname: Srikanth
authors.forename: Sylvie
authors.initials: S
authors.lastname: Giroux
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.forename: Hou-Feng
authors.initials: HF
authors.lastname: Zheng
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Pye
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Hwang
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Fiona
authors.initials: F
authors.lastname: McGuigan
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Minster
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: José M
authors.initials: JM
authors.lastname: Olmos
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Lewis
authors.forename: Karin M A
authors.initials: KM
authors.lastname: Swart
authors.forename: Laura
authors.initials: L
authors.lastname: Masi
authors.forename: Chris
authors.initials: C
authors.lastname: Oldmeadow
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.forename: Sulin
authors.initials: S
authors.lastname: Cheng
authors.forename: Natasja M
authors.initials: NM
authors.lastname: van Schoor
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Harvey
authors.forename: Marcin
authors.initials: M
authors.lastname: Kruk
authors.forename: Fabiola
authors.initials: F
authors.lastname: del Greco M
authors.forename: Wilmar
authors.initials: W
authors.lastname: Igl
authors.forename: Olivia
authors.initials: O
authors.lastname: Trummer
authors.forename: Efi
authors.initials: E
authors.lastname: Grigoriou
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhou
authors.forename: Ling
authors.initials: L
authors.lastname: Oei
authors.forename: Carolina
authors.initials: C
authors.lastname: Medina-Gomez
authors.forename: Joseph
authors.initials: J
authors.lastname: Zmuda
authors.forename: Greg
authors.initials: G
authors.lastname: Tranah
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Frances M
authors.initials: FM
authors.lastname: Williams
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Johanna
authors.initials: J
authors.lastname: Jakobsdottir
authors.forename: Kristin
authors.initials: K
authors.lastname: Siggeirsdottir
authors.forename: Kate L
authors.initials: KL
authors.lastname: Holliday
authors.forename: Anke
authors.initials: A
authors.lastname: Hannemann
authors.forename: Min Jin
authors.initials: MJ
authors.lastname: Go
authors.forename: Melissa
authors.initials: M
authors.lastname: Garcia
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.forename: Marika
authors.initials: M
authors.lastname: Laaksonen
authors.forename: Kun
authors.initials: K
authors.lastname: Zhu
authors.forename: Anke W
authors.initials: AW
authors.lastname: Enneman
authors.forename: Mark
authors.initials: M
authors.lastname: McEvoy
authors.forename: Roseanne
authors.initials: R
authors.lastname: Peel
authors.forename: Pak Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Maciej
authors.initials: M
authors.lastname: Jaworski
authors.forename: Åsa
authors.initials: Å
authors.lastname: Johansson
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.forename: Pawel
authors.initials: P
authors.lastname: Pludowski
authors.forename: Rodney
authors.initials: R
authors.lastname: Scott
authors.forename: Rosalie A M
authors.initials: RA
authors.lastname: Dhonukshe-Rutten
authors.forename: Nathalie
authors.initials: N
authors.lastname: van der Velde
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Jorma S
authors.initials: JS
authors.lastname: Viikari
authors.forename: Harri
authors.initials: H
authors.lastname: Sievänen
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.forename: Jesús
authors.initials: J
authors.lastname: González-Macías
authors.forename: Jose L
authors.initials: JL
authors.lastname: Hernández
authors.forename: Dan
authors.initials: D
authors.lastname: Mellström
authors.forename: Osten
authors.initials: O
authors.lastname: Ljunggren
authors.forename: Yoon Shin
authors.initials: YS
authors.lastname: Cho
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Robin
authors.initials: R
authors.lastname: Haring
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
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: John A
authors.initials: JA
authors.lastname: Eisman
authors.forename: Graeme
authors.initials: G
authors.lastname: Jones
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: Steven
authors.initials: S
authors.lastname: Boonen
authors.forename: Dirk
authors.initials: D
authors.lastname: Vanderschueren
authors.forename: Frederick C W
authors.initials: FC
authors.lastname: Wu
authors.forename: Thor
authors.initials: T
authors.lastname: Aspelund
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.forename: Doug
authors.initials: D
authors.lastname: Bauer
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: George
authors.initials: G
authors.lastname: Dedoussis
authors.forename: Barbara
authors.initials: B
authors.lastname: Obermayer-Pietsch
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Roman S
authors.initials: RS
authors.lastname: Lorenc
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.forename: Annie Wai Chee
authors.initials: AW
authors.lastname: Kung
authors.forename: Paul
authors.initials: P
authors.lastname: Lips
authors.forename: Markku
authors.initials: M
authors.lastname: Alen
authors.forename: John
authors.initials: J
authors.lastname: Attia
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Brandi
authors.forename: Lisette C P G M
authors.initials: LC
authors.lastname: de Groot
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: José A
authors.initials: JA
authors.lastname: Riancho
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Kristina
authors.initials: K
authors.lastname: Akesson
authors.forename: Magnus
authors.initials: M
authors.lastname: Karlsson
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Henri
authors.initials: H
authors.lastname: Wallaschofski
authors.forename: Emma L
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authors.lastname: Duncan
authors.forename: Terence W
authors.initials: TW
authors.lastname: O'Neill
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: François
authors.initials: F
authors.lastname: Rousseau
authors.forename: Eric
authors.initials: E
authors.lastname: Orwoll
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Richard L
authors.initials: RL
authors.lastname: Prince
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Reeve
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Kaptoge
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D002111:Calcaneus / Q000000981:diagnostic imaging* / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D050723:Fractures, Bone / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D014463:Ultrasonography; D055815:Young Adult