Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Research output: Contribution to journalArticle

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 x 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 x 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 x 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.

Details

Authors
  • Alireza Moayyeri
  • Yi-Hsiang Hsu
  • David Karasik
  • Karol Estrada
  • Su-Mei Xiao
  • Carrie Nielson
  • Priya Srikanth
  • Sylvie Giroux
  • Scott G. Wilson
  • Hou-Feng Zheng
  • Albert V. Smith
  • Stephen R. Pye
  • Paul J. Leo
  • Alexander Teumer
  • Joo-Yeon Hwang
  • Claes Ohlsson
  • Ryan L. Minster
  • Caroline Hayward
  • Jose M. Olmos
  • Leo-Pekka Lyytikaeinen
  • Joshua R. Lewis
  • Karin M. A. Swart
  • Laura Masi
  • Chris Oldmeadow
  • Elizabeth G. Holliday
  • Sulin Cheng
  • Natasja M. van Schoor
  • Nicholas C. Harvey
  • Marcin Kruk
  • M. Fabiola Del Greco
  • Wilmar Igl
  • Olivia Trummer
  • Efi Grigoriou
  • Robert Luben
  • Ching-Ti Liu
  • Yanhua Zhou
  • Ling Oei
  • Carolina Medina-Gomez
  • Joseph Zmuda
  • Greg Tranah
  • Suzanne J. Brown
  • Frances M. Williams
  • Nicole Soranzo
  • Johanna Jakobsdottir
  • Kristin Siggeirsdottir
  • Kate L. Holliday
  • Anke Hannemann
  • Min Jin Go
  • Melissa Garcia
  • Ozren Polasek
  • Marika Laaksonen
  • Kun Zhu
  • Anke W. Enneman
  • Mark McEvoy
  • Roseanne Peel
  • Pak Chung Sham
  • Maciej Jaworski
  • Asa Johansson
  • Andrew A. Hicks
  • Pawel Pludowski
  • Rodney Scott
  • Rosalie A. M. Dhonukshe-Rutten
  • Nathalie van der Velde
  • Mika Kaehoenen
  • Jorma S. Viikari
  • Harri Sievaenen
  • Olli T. Raitakari
  • Jesus Gonzalez-Macias
  • Jose L. Hernandez
  • Dan Mellstroem
  • Oesten Ljunggren
  • Yoon Shin Cho
  • Uwe Voelker
  • Matthias Nauck
  • Georg Homuth
  • Henry Voelzke
  • Robin Haring
  • Matthew A. Brown
  • Eugene McCloskey
  • Geoffrey C. Nicholson
  • Richard Eastell
  • John A. Eisman
  • Graeme Jones
  • Ian R. Reid
  • Elaine M. Dennison
  • John Wark
  • Steven Boonen
  • Dirk Vanderschueren
  • Frederick C. W. Wu
  • Thor Aspelund
  • J. Brent Richards
  • Doug Bauer
  • Albert Hofman
  • Kay-Tee Khaw
  • George Dedoussis
  • Barbara Obermayer-Pietsch
  • Ulf Gyllensten
  • Peter P. Pramstaller
  • Roman S. Lorenc
  • Cyrus Cooper
  • Annie Wai Chee Kung
  • Paul Lips
  • Markku Alen
  • John Attia
  • Maria Luisa Brandi
  • Lisette C. P. G. M. de Groot
  • Terho Lehtimaeki
  • Jose A. Riancho
  • Harry Campbell
  • Yongmei Liu
  • Tamara B. Harris
  • Jong-Young Lee
  • Henri Wallaschofski
  • Emma L. Duncan
  • Terence W. O'Neill
  • Vilmundur Gudnason
  • Timothy D. Spector
  • Francois Rousseau
  • Eric Orwoll
  • Steven R. Cummings
  • Nick J. Wareham
  • Fernando Rivadeneira
  • Andre G. Uitterlinden
  • Richard L. Prince
  • Douglas P. Kiel
  • Jonathan Reeve
  • Stephen K. Kaptoge
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)3054-3068
JournalHuman Molecular Genetics
Volume23
Issue number11
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes