Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Research output: Contribution to journalArticle

  • Authors:
  • Karol Estrada
  • Unnur Styrkarsdottir
  • Evangelos Evangelou
  • Yi Hsiang Hsu
  • Emma L. Duncan
  • And 176 others
  • External authors:
  • Evangelia E. Ntzani
  • Ling Oei
  • Omar M E Albagha
  • Najaf Amin
  • John P. Kemp
  • Daniel L. Koller
  • Guo Li
  • Ching Ti Liu
  • Ryan L. Minster
  • Alireza Moayyeri
  • Liesbeth Vandenput
  • Dana Willner
  • Su Mei Xiao
  • Laura M. Yerges-Armstrong
  • Hou Feng Zheng
  • Nerea Alonso
  • Joel Eriksson
  • Candace M. Kammerer
  • Stephen K. Kaptoge
  • Paul J. Leo
  • Gudmar Thorleifsson
  • Scott G. Wilson
  • James F. Wilson
  • Ville Aalto
  • Markku Alen
  • Aaron K. Aragaki
  • Thor Aspelund
  • Jacqueline R. Center
  • Zoe Dailiana
  • David J. Duggan
  • Melissa Garcia
  • Natàlia Garcia-Giralt
  • Sylvie Giroux
  • Göran Hallmans
  • Lynne J. Hocking
  • Lise Bjerre Husted
  • Karen A. Jameson
  • Rita Khusainova
  • Ghi Su Kim
  • Charles Kooperberg
  • Theodora Koromila
  • Marcin Kruk
  • Marika Laaksonen
  • Andrea Z. Lacroix
  • Seung Hun Lee
  • Ping C. Leung
  • Joshua R. Lewis
  • Laura Masi
  • Simona Mencej-Bedrac
  • Tuan V. Nguyen
  • Xavier Nogues
  • Millan S. Patel
  • Janez Prezelj
  • Lynda M. Rose
  • Serena Scollen
  • Kristin Siggeirsdottir
  • Albert V. Smith
  • Olle Svensson
  • Stella Trompet
  • Olivia Trummer
  • Natasja M. Van Schoor
  • Jean Woo
  • Kun Zhu
  • Susana Balcells
  • Maria Luisa Brandi
  • Brendan M. Buckley
  • Sulin Cheng
  • Claus Christiansen
  • Cyrus Cooper
  • George Dedoussis
  • Ian Ford
  • Morten Frost
  • David Goltzman
  • Jesús González-Macías
  • Mika Kähönen
  • Magnus Karlsson
  • Elza Khusnutdinova
  • Jung Min Koh
  • Panagoula Kollia
  • Bente Lomholt Langdahl
  • William D. Leslie
  • Paul Lips
  • Østen Ljunggren
  • Roman S. Lorenc
  • Janja Marc
  • Dan Mellström
  • Barbara Obermayer-Pietsch
  • José M. Olmos
  • Ulrika Pettersson-Kymmer
  • David M. Reid
  • José A. Riancho
  • Paul M. Ridker
  • François Rousseau
  • P. Eline S Lagboom
  • Nelson L S Tang
  • Roser Urreizti
  • Wim Van Hul
  • Jorma Viikari
  • María T. Zarrabeitia
  • Yurii S. Aulchenko
  • Martha Castano-Betancourt
  • Elin Grundberg
  • Lizbeth Herrera
  • Thorvaldur Ingvarsson
  • Hrefna Johannsdottir
  • Tony Kwan
  • Rui Li
  • Robert Luben
  • Carolina Medina-Gómez
  • Stefan Th Palsson
  • Sjur Reppe
  • Jerome I. Rotter
  • Gunnar Sigurdsson
  • Joyce B J Van Meurs
  • Dominique Verlaan
  • Frances M K Williams
  • Andrew R. Wood
  • Yanhua Zhou
  • Kaare M. Gautvik
  • Tomi Pastinen
  • Soumya Raychaudhuri
  • Jane A. Cauley
  • Daniel I. Chasman
  • Graeme R. Clark
  • Steven R. Cummings
  • Patrick Danoy
  • Elaine M. Dennison
  • Richard Eastell
  • John A. Eisman
  • Vilmundur Gudnason
  • Albert Hofman
  • Rebecca D. Jackson
  • Graeme Jones
  • J. Wouter Jukema
  • Kay Tee Khaw
  • Terho Lehtimäki
  • Yongmei Liu
  • Mattias Lorentzon
  • Eugene Mccloskey
  • Braxton D. Mitchell
  • Kannabiran Nandakumar
  • Geoffrey C. Nicholson
  • Ben A. Oostra
  • Munro Peacock
  • Huibert A P Pols
  • Richard L. Prince
  • Olli Raitakari
  • Ian R. Reid
  • John Robbins
  • Philip N. Sambrook
  • Pak Chung Sham
  • Alan R. Shuldiner
  • Frances A. Tylavsky
  • Cornelia M. Van Duijn
  • Nick J. Wareham
  • L. Adrienne Cupples
  • Michael J. Econs
  • David M. Evans
  • Tamara B. Harris
  • Annie Wai Chee Kung
  • Bruce M. Psaty
  • Jonathan Reeve
  • Timothy D. Spector
  • Elizabeth A. Streeten
  • M. Carola Zillikens
  • Unnur Thorsteinsdottir
  • Claes Ohlsson
  • David Karasik
  • J. Brent Richards
  • Matthew A. Brown
  • Kari Stefansson
  • André G. Uitterlinden
  • Stuart H. Ralston
  • John P A Ioannidis
  • Douglas P. Kiel
  • Fernando Rivadeneira

Abstract

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P <5 × 10 -8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P <5 × 10 -4, Bonferroni corrected), of which six reached P <5 × 10 -8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. © 2012 Nature America, Inc. All rights reserved.

Bibliographical metadata

Original languageEnglish
Pages (from-to)491-501
Number of pages10
JournalNature Genetics
Volume44
Issue number5
DOIs
Publication statusPublished - May 2012