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

Journal article
Authors Karol Estrada
Unnur Styrkarsdottir
Evangelos Evangelou
Yi-Hsiang Hsu
Emma L Duncan
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
Natalia 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
Jesus Gonzalez-Macias
Mika Kähönen
Magnus Karlsson
Elza Khusnutdinova
Jung-Min Koh
Panagoula Kollia
Bente Lomholt Langdahl
William D Leslie
Paul Lips
Östen 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 Slagboom
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-Gomez
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
Andre G Uitterlinden
Stuart H Ralston
John P A Ioannidis
Douglas P Kiel
Fernando Rivadeneira
Published in Nature genetics
Volume 44
Issue 5
Pages 491-501
ISSN 1546-1718
Publication year 2012
Published at Centre for Bone and Arthritis Research
Pages 491-501
Language en
Links dx.doi.org/10.1038/ng.2249
Keywords Bone Density, genetics, Computational Biology, European Continental Ancestry Group, Extracellular Matrix Proteins, genetics, Female, Femur Neck, physiopathology, Fractures, Bone, genetics, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycoproteins, genetics, Humans, Intercellular Signaling Peptides and Proteins, genetics, Low Density Lipoprotein Receptor-Related Protein-5, genetics, Lumbar Vertebrae, physiopathology, Male, Mitochondrial Membrane Transport Proteins, genetics, Osteoporosis, genetics, Phosphoproteins, genetics, Polymorphism, Single Nucleotide, genetics, Quantitative Trait Loci, Risk Factors, Spectrin, genetics
Subject categories Endocrinology, Internal medicine

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.

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