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

TLDR: Light is shed on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility and within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways.

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.

Full text

Edinburgh Research Explorer
Genome-wide meta-analysis identifies 56 bone mineral density
loci and reveals 14 loci associated with risk of fracture
Citation for published version:
Estrada, K, Styrkarsdottir, U, Evangelou, E, Hsu, Y-H, Duncan, EL, Ntzani, EE, Oei, L, Albagha, OME,
Amin, N, Kemp, JP, Koller, DL, Li, G, Liu, C-T, Minster, RL, Moayyeri, A, Vandenput, L, Willner, D, Xiao, S-
M, Yerges-Armstrong, LM, Zheng, H-F, Alonso, N, Eriksson, J, Kammerer, CM, Kaptoge, SK, Leo, PJ,
Thorleifsson, G, Wilson, SG, Wilson, JF, Aalto, V, Alen, M, Aragaki, AK, Aspelund, T, Center, JR, Dailiana,
Z, Duggan, DJ, Garcia, M, Garcia-Giralt, N, Giroux, S, Hallmans, G, Hocking, LJ, Husted, LB, Jameson, KA,
Khusainova, R, Kim, GS, Kooperberg, C, Koromila, T, Kruk, M, Laaksonen, M, Lacroix, AZ, Lee, SH, Leung,
PC, Lewis, JR, Masi, L, Mencej-Bedrac, S, Nguyen, TV, Nogues, X, Patel, MS, Prezelj, J, Rose, LM,
Scollen, S, Siggeirsdottir, K, Smith, AV, Svensson, O, Trompet, S, Trummer, O, van Schoor, NM, Woo, J,
Zhu, K, Balcells, S, Brandi, ML, Buckley, BM, Cheng, S, Christiansen, C, Cooper, C, Dedoussis, G, Ford, I,
Frost, M, Goltzman, D, González-Macías, J, Kähönen, M, Karlsson, M, Khusnutdinova, E, Koh, J-M, Kollia,
P, Langdahl, BL, Leslie, WD, Lips, P, Ljunggren, Ö, Lorenc, RS, Marc, J, Mellström, D, Obermayer-Pietsch,
B, Olmos, JM, Pettersson-Kymmer, U, Reid, DM, Riancho, JA, Ridker, PM, Rousseau, F, Slagboom, PE,
Tang, NLS, Urreizti, R, Van Hul, W, Viikari, J, Zarrabeitia, MT, Aulchenko, YS, Castano-Betancourt, M,
Grundberg, E, Herrera, L, Ingvarsson, T, Johannsdottir, H, Kwan, T, Li, R, Luben, R, Medina-Gómez, C,
Palsson, ST, Reppe, S, Rotter, JI, Sigurdsson, G, van Meurs, JBJ, Verlaan, D, Williams, FMK, Wood, A,
Zhou, Y, Gautvik, KM, Pastinen, T, Raychaudhuri, S, Cauley, JA, Chasman, DI, Clark, GR, Cummings, SR,
Danoy, P, Dennison, EM, Eastell, R, Eisman, JA, Gudnason, V, Hofman, A, Jackson, RD, Jones, G,
Jukema, JW, Khaw, K-T, Lehtimäki, T, Liu, Y, Lorentzon, M, McCloskey, E, Mitchell, BD, Nandakumar, K,
Nicholson, GC, Oostra, BA, Peacock, M, Pols, HAP, Prince, RL, Raitakari, O, Reid, IR, Robbins, J,
Sambrook, PN, Sham, PC, Shuldiner, AR, Tylavsky, FA, van Duijn, CM, Wareham, NJ, Cupples, LA, Econs,
MJ, Evans, DM, Harris, TB, Kung, AWC, Psaty, BM, Reeve, J, Spector, TD, Streeten, EA, Zillikens, MC,
Thorsteinsdottir, U, Ohlsson, C, Karasik, D, Richards, JB, Brown, MA, Stefansson, K, Uitterlinden, AG,
Ralston, SH, Ioannidis, JPA, Kiel, DP & Rivadeneira, F 2012, 'Genome-wide meta-analysis identifies 56
bone mineral density loci and reveals 14 loci associated with risk of fracture', Nature Genetics, vol. 44, no.
5, pp. 491-501. https://doi.org/10.1038/ng.2249
Digital Object Identifier (DOI):
10.1038/ng.2249
Link:
Link to publication record in Edinburgh Research Explorer
Document Version:
Peer reviewed version
Published In:
Nature Genetics
Publisher Rights Statement:
© 2012 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Genome-wide meta-analysis identifies 56 bone mineral density
loci and reveals 14 loci associated with risk of fracture
Karol Estrada
1,2,3,139
, Unnur Styrkarsdottir
4,139
, Evangelos Evangelou
5,139
, Yi-Hsiang
Hsu
6,7,139
, Emma L Duncan
8,9,139
, Evangelia E Ntzani
5,139
, Ling Oei
1,2,3,139
, Omar M E
Correspondence should be addressed to: Dr. Fernando Rivadeneira M.D., Ph.D., Genetic Laboratory - Room Ee 579, Department of
Internal Medicine, Erasmus MC PO Box 2040, 3000CA Rotterdam, The Netherlands, f.rivadeneira@erasmusmc.nl.
139
These authors contributed equally to this work.
140
These authors jointly directed this work.
Author Contributions
This work was done under the auspices of the European Commission sponsored Genetic Factors for Osteoporosis (GEFOS)
consortium.
Study-specific design and management: U.S., M.A., L.M., J.P., S.B., M.B., B.M.B., C. Christiansen, C. Cooper, G.D., I.F., M.F.,
D.G., J.G-M., M. Kähönen, M. Karlsson, J-M.K., P.K., B.L.L., W.D.L., P.L., Ö.L., R.S.L., J.M., D.M., J.M.O., U.P., J.A.R., P.M.R.,
F. Rousseau, P.E.S., N.L.T., R.U., W.V., J.V., M.T.Z., K.M.G., T.P., D.I.C., S.R.C., R.E., J.A.E., V.G., A.H., R.D.J., G.J., J.W.J., K-
T.K., T.L., M. Lorentzon, E.M., B.D.M., G.C.N., M.P., H.A.P., R.L.P., O.R., I.R.R., P.N.S., P.C.S., A.R.S., F.A.T., C.M.D., N.J.W.,
L.A.C., M.J.E., T.B.H., A.W-C.K., B.M.P., J. Reeve, T.D.S., E.A.S., M.Z., U.T., C.O., J.B.R., M.A.B., K. Stefansson, A.G.U., S.H.R.,
J.P.I., D.P.K. and F. Rivadeneira.
Study-specific Genotyping: K.E., U.S., E.L.D., L.O., L.V., S.X., A.K.A., D.J.D., S.G., R.K., C.K., A.Z.L., J.R.L., S.M., S.S., S.T.,
O.T., S.C., E.K., J.M., B.O-P., Y.S.A., E.G., L.H., H.J., T. Kwan, R. Luben, C.M., S.T.P., S. Reppe, J.I.R., J.B.v., D.V., K.M.G.,
D.I.C., G.R.C., P.D., R.D.J., T.L., Y.L., M. Lorentzon, R.L.P., N.J.W., L.A.C., C.O., M.A.B., A.G.U. and F. Rivadeneira.
Study-specific Phenotyping: U.S., E.L.D., O.M.A., A.M., S.X., N. Alonso, S.K.K., S.G.W., A.K.A., T.A., J.R.C., Z.D., N.G-G.,
S.G., G.H., L.B.H., K.A.J., G.K., C.K., T. Koromila, M. Kruk, M. Laaksonen, A.Z.L., S.L., P.C.L., L.M., X.N., J.P., L.M.R., K.
Siggeirsdottir, O.S., N.M.v., J.W., K.Z., M.B., C. Christiansen, M.F., M. Kähönen, M. Karlsson, J-M.K., Ö.L., J.M., D.M., B.O-P.,
J.M.O., U.P., D.M.R., J.A.R., P.M.R., F. Rousseau, W.V., J.V., M.C-B., E.G., T.I., R. Luben, S. Reppe, G.S., J.B.v., D.V., F.M.W.,
K.M.G., J.A.C., D.I.C., E.M.D., R.E., J.A.E., V.G., A.H., R.D.J., G.J., Y.L., M. Lorentzon, E.M., G.C.N., B.A.O., M.P., H.A.P.,
R.L.P., O.R., I.R.R., J. Robbins, P.N.S., C.M.D., M.J.E., J. Reeve, E.A.S., M.Z., C.O., M.A.B., A.G.U., D.P.K. and F. Rivadeneira.
Study-specific data analysis: K.E., U.S., E.E., Y.H., E.L.D., E.E.N., L.O., O.M.A., N. Amin, J.P.K., D.L.K., G.L., C.L., R.L.M.,
A.M., L.V., D.W., S.X., L.M.Y-A., H.Z., J.E., C.M.K., S.K.K., P.J.L., G.T., J.F.W., V.A., A.K.A., T.A., J.R.C., G.H., L.J.H., C.K., T.
Koromila, A.Z.L., S.M., T.V.N., M.S.P., J.P., L.M.R., A.V.S., O.S., S.T., S.C., J.M., B.O-P., U.P., R. Li, R. Luben, S. Reppe, J.I.R.,
A.R.W., Y.Z., S. Raychaudhuri, D.I.C., J.A.E., R.D.J., T.L., K.N., O.R., D.M.E., D.K., J.B.R., M.A.B., J.P.I., D.P.K. and F.
Rivadeneira.
Analysis plan design: K.E., E.E., U.S. D.K., D.P.K, J.P.I. and F. Rivadeneira.
Meta-analyses: K.E., E.E., Y.H. and E.E.N.
Gene by Gene interaction: K.E., E.E. and A.R.W.
Risk modeling and secondary signals: K.E. and F. Rivadeneira.
Expression QTL: U.S., G.T., E.G., S. Reppe, K.M.G. and T.P.
Functional SNP prediction: Y.H.
Gene relationships across implicated loci (GRAIL): K.E., E.L.D., D.W. and S. Raychaudhuri.
Standardization of phenotype and genotype replication datasets: K.E., U.S., E.E., E.L.D., L.O., G.T., L.H. and C.M.
Interpretation of results (BMD working group): K.E., U.S., E.E., Y.H., E.L.D., E.E.N., L.O., O.M.A., N. Amin, D.L.K., C.L.,
R.L.M., A.M., L.V., D.W., S.X., L.M.Y-A., J.E., C.M.K., S.K.K., A.W-C.K., J. Reeve, M.Z., C.O., D.K., J.B.R., M.A.B., A.G.U.,
S.H.R., J.P.I., D.P.K. and F. Rivadeneira.
Manuscript draft (BMD writing group): K.E., U.S., E.E., Y.H., E.L.D., E.E.N., L.O., O.M.A., A.M., C.O., D.K., J.B.R., M.A.B.,
A.G.U., S.H.R., J.P.I., D.P.K. and F. Rivadeneira.
GEFOS Steering committee: U.S., E.E., U.T., A.G.U., S.H.R., J.P.I. and F. Rivadeneira.
Competing financial interests
The coauthors affiliated with deCODE Genetics in Reykjavík Iceland withhold stock options in that company.
URLs
GEFOS Consortium, http://www.gefos.org/;
GENOMOS Consortium, http://www.genomos.eu/;
HapMap Project, http://hapmap.ncbi.nlm.nih.gov/;
1000 Genomes Project, http://www.1000genomes.org/;
LocusZoom, http://csg.sph.umich.edu/locuszoom/;
METAL, http://www.sph.umich.edu/csg/abecasis/Metal/
NIH Public Access
Author Manuscript
Nat Genet
. Author manuscript; available in PMC 2012 November 01.
Published in final edited form as:
Nat Genet
. ; 44(5): 491–501. doi:10.1038/ng.2249.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Albagha
10
, Najaf Amin
2
, John P Kemp
11
, Daniel L Koller
12
, Guo Li
13
, Ching-Ti Liu
14
, Ryan L
Minster
15
, Alireza Moayyeri
16,17
, Liesbeth Vandenput
18
, Dana Willner
8,19
, Su-Mei Xiao
20,21
,
Laura M Yerges-Armstrong
22
, Hou-Feng Zheng
23
, Nerea Alonso
10
, Joel Eriksson
18
,
Candace M Kammerer
15
, Stephen K Kaptoge
16
, Paul J Leo
8
, Gudmar Thorleifsson
4
, Scott
G Wilson
17,24,25
, James F Wilson
26,27
, Ville Aalto
28,29
, Markku Alen
30
, Aaron K Aragaki
31
,
Thor Aspelund
32,33
, Jacqueline R Center
34,35,36
, Zoe Dailiana
37
, David J Duggan
38
, Melissa
Garcia
39
, Natàlia Garcia-Giralt
40
, Sylvie Giroux
41
, Göran Hallmans
42
, Lynne J Hocking
43
,
Lise Bjerre Husted
44
, Karen A Jameson
45
, Rita Khusainova
46,47
, Ghi Su Kim
48
, Charles
Kooperberg
31
, Theodora Koromila
49
, Marcin Kruk
50
, Marika Laaksonen
51
, Andrea Z
Lacroix
31
, Seung Hun Lee
48
, Ping C Leung
52
, Joshua R Lewis
24,25
, Laura Masi
53
, Simona
Mencej-Bedrac
54
, Tuan V Nguyen
34,35
, Xavier Nogues
40
, Millan S Patel
55
, Janez Prezelj
56
,
Lynda M Rose
57
, Serena Scollen
58
, Kristin Siggeirsdottir
32
, Albert V Smith
32,33
, Olle
Svensson
59
, Stella Trompet
60,61
, Olivia Trummer
62
, Natasja M van Schoor
63
, Jean Woo
64
,
Kun Zhu
24,25
, Susana Balcells
65
, Maria Luisa Brandi
53
, Brendan M Buckley
66
, Sulin
Cheng
67,68
, Claus Christiansen
69
, Cyrus Cooper
45
, George Dedoussis
70
, Ian Ford
71
,
Morten Frost
72,73
, David Goltzman
74
, Jesús González-Macías
75,76
, Mika Kähönen
77,78
,
Magnus Karlsson
79
, Elza Khusnutdinova
46,47
, Jung-Min Koh
48
, Panagoula Kollia
49
, Bente
Lomholt Langdahl
44
, William D Leslie
80
, Paul Lips
81,82
, Östen Ljunggren
83
, Roman S
Lorenc
50
, Janja Marc
54
, Dan Mellström
18
, Barbara Obermayer-Pietsch
62
, José M
Olmos
75,76
, Ulrika Pettersson-Kymmer
84
, David M Reid
43
, José A Riancho
75,76
, Paul M
Ridker
57,85
, François Rousseau
41,86,87
, P Eline Slagboom
88,3
, Nelson LS Tang
89,90
, Roser
Urreizti
65
, Wim Van Hul
91
, Jorma Viikari
92,93
, María T Zarrabeitia
94
, Yurii S Aulchenko
2
,
Martha Castano-Betancourt
1,2,3
, Elin Grundberg
95,96,97
, Lizbeth Herrera
1
, Thorvaldur
Ingvarsson
98,99,33
, Hrefna Johannsdottir
4
, Tony Kwan
95,96
, Rui Li
100
, Robert Luben
16
,
Carolina Medina-Gómez
1,2
, Stefan Th Palsson
4
, Sjur Reppe
101
, Jerome I Rotter
102
, Gunnar
Sigurdsson
103,33
, Joyce B J van Meurs
1,2,3
, Dominique Verlaan
95,96
, Frances MK
Williams
17
, Andrew R Wood
104
, Yanhua Zhou
14
, Kaare M Gautvik
101,105,106
, Tomi
Pastinen
95,96,107
, Soumya Raychaudhuri
108,109
, Jane A Cauley
110
, Daniel I Chasman
57,85
,
Graeme R Clark
8
, Steven R Cummings
111
, Patrick Danoy
8
, Elaine M Dennison
45
, Richard
Eastell
112
, John A Eisman
34,35,36
, Vilmundur Gudnason
32,33
, Albert Hofman
2,3
, Rebecca D
Jackson
113,114
, Graeme Jones
115
, J Wouter Jukema
60,116,117
, Kay-Tee Khaw
16
, Terho
Lehtimäki
118,119
, Yongmei Liu
120
, Mattias Lorentzon
18
, Eugene McCloskey
112,121
, Braxton
D Mitchell
22
, Kannabiran Nandakumar
6,7
, Geoffrey C Nicholson
122
, Ben A Oostra
123
, Munro
Peacock
124
, Huibert A P Pols
1,2
, Richard L Prince
24,25
, Olli Raitakari
28,29
, Ian R Reid
125
,
John Robbins
126
, Philip N Sambrook
127
, Pak Chung Sham
128,129
, Alan R Shuldiner
22,130
,
Frances A Tylavsky
131
, Cornelia M van Duijn
2
, Nick J Wareham
132
, L Adrienne
Cupples
14,133
, Michael J Econs
124,12
, David M Evans
11
, Tamara B Harris
39
, Annie Wai Chee
Kung
20,21
, Bruce M Psaty
134,135
, Jonathan Reeve
136
, Timothy D Spector
17
, Elizabeth A
Streeten
22,130
, M Carola Zillikens
1
, Unnur Thorsteinsdottir
4,33,140
, Claes Ohlsson
18,140
,
David Karasik
6,7,140
, J Brent Richards
137,17,140
, Matthew A Brown
8,140
, Kari
Stefansson
4,33,140
, André G Uitterlinden
1,2,3,140
, Stuart H Ralston
10,140
, John P A
Ioannidis
138,5,140
, Douglas P Kiel
6,7,140
, and Fernando Rivadeneira
1,2,3,140
1
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
2
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
3
Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging
(NCHA), Leiden, The Netherlands
4
deCODE Genetics, Reykjavik, Iceland
5
Department of
Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece
6
Institute for Aging
Research, Hebrew SeniorLife, Boston, USA
7
Department of Medicine, Harvard Medical School,
Boston, USA
8
Human Genetics Group, University of Queensland Diamantina Institute, Brisbane,
Australia
9
Department of Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane,
Australia
10
Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of
Estrada et al.
Page 2
Nat Genet
. Author manuscript; available in PMC 2012 November 01.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Edinburgh, Edinburgh, UK
11
Medical Research Council (MRC) Centre for Causal Analyses in
Translational Epidemiology, University of Bristol, Bristol, UK
12
Department of Medical and
Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA
13
Cardiovascular
Health Research Unit, University of Washington, Seattle, USA
14
Department of Biostatistics,
Boston University School of Public Health, Boston, USA
15
Department of Human Genetics,
University of Pittsburgh, Pittsburgh, PA, USA
16
of Public Health and Primary Care, University of
Cambridge, Cambridge, UK
17
Department of Twin Research and Genetic Epidemiology, King’s
College London, London, UK
18
Centre for Bone and Arthritis Research, Institute of Medicine,
Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
19
Australian Centre for
Ecogenomics, University of Queensland, Brisbane, Australia
20
Department of Medicine, The
University of Hong Kong, Hong Kong, China
21
Research Centre of Heart, Brain, Hormone and
Healthy Aging, The University of Hong Kong, Hong Kong, China
22
Department of Medicine,
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine,
Baltimore, MD, USA
23
Department of Human Genetics, Lady Davis Institute, McGill University,
Montreal, Canada
24
School of Medicine and Pharmacology, University of Western Australia,
Perth, Australia
25
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital,
Perth, Australia
26
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
27
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University
of Edinburgh, Edinburgh, UK
28
Department of Clinical Physiology, Turku University Hospital,
Turku, Finland
29
Research Centre of Applied and Preventive Cardiovascular Medicine, University
of Turku, Turku, Finland
30
Department of Medical Rehabilitation, Oulu University Hospital and
Institute of Health Sciences, Oulu, Finland
31
Division of Public Health Sciences, Fred Hutchinson
Cancer Research Center, Seattle, USA
32
Icelandic Heart Association, Kopavogur, Iceland
33
Faculty of Medicine, University of Iceland, Reykjavik, Iceland
34
Osteoporosis and Bone Biology
Program, Garvan Institute of Medical Research, Sydney, Australia
35
Department of Medicine,
University of New South Wales, Sydney, Australia
36
Department of Endocrinology, St Vincents
Hospital, Sydney, Australia
37
Department of Orthopaedic Surgery, Medical School University of
Thessalia, Larissa, Greece
38
Translational Genomics Research Institute, Phoenix, USA
39
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda,
MD, USA
40
Department of Internal Medicine, Hospital del Mar, Instituto Municipal de
Investigación Médica (IMIM), Red Temática de Investigación Cooperativa en Envejecimiento y
Fragilidad (RETICEF), Universitat Autònoma de Barcelona (UAB), Barcelone, Spain
41
Unité de
recherche en génétique humaine et moléculaire, Centre de recherche du Centre hospitalier
universitaire de Québec - Hôpital St-François-d’Assise (CHUQ/HSFA), Québec City, Canada
42
Department of Public Health and Clinical Medicine, Umeå Unviersity, Umeå, Sweden
43
Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen,
Aberdeen, UK
44
Department of Endocrinology and Internal Medicine, Aarhus University Hospital,
Aarhus C, Denmark
45
MRC Lifecourse Epidemiology Unit, University of Southampton,
Southampton, UK
46
Ufa Scientific Centre of Russian Academy of Sciences, Institute of
Biochemistry and Genetics, Ufa, Russia
47
Biological Department, Bashkir State University, Ufa,
Russia
48
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, South Korea
49
Department of Genetics and Biotechnology, Faculty of
Biology, University of Athens, Athens, Greece
50
Department of Biochemistry and Experimental
Medicine, The Children’s Memorial Health Institute, Warsaw, Poland
51
Department of Food and
Environmental Sciences, University of Helsinki, Helsinki, Finland
52
Jockey Club Centre for
Osteoporosis Care and Control, The Chinese University of Hong Kong, Hong Kong SAR, China
53
Department of Internal Medicine, University of Florence, Florence, Italy
54
Department of Clinical
Biochemistry, University of Ljubljana, Ljubljana, Slovenia
55
Department of Medical Genetics,
University of British Columbia, Vancouver, Canada
56
Department of Endocrinology, University
Medical Center, Ljubljana, Slovenia
57
Division of Preventive Medicine, Brigham and Women’s
Hospital, Boston, USA
58
Department of Medicine, University of Cambridge, Cambridge, UK
Estrada et al.
Page 3
Nat Genet
. Author manuscript; available in PMC 2012 November 01.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

59
Department of Surgical and Perioperative Sciences, Umeå Unviersity, Umeå, Sweden
60
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
61
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The
Netherlands
62
Department of Internal Medicine, Division of Endocrinology and Metabolism,
Medical University Graz, Graz, Austria
63
Department of Epidemiology and Biostatistics,
Extramuraal Geneeskundig Onderzoek (EMGO) Institute for Health and Care Research, Vrije
Universiteit (VU) University Medical Center, Amsterdam, The Netherlands
64
Department of
Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
65
Department of Genetics, University of Barcelona, Centro de Investigación Biomédica en Red de
Enfermedades Raras (CIBERER), Institut de Biomedicina de la Universitat de Barcelona (IBUB),
Barcelone, Spain
66
Department of Pharmacology and Therapeutics, University College Cork,
Cork, Ireland
67
Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland
68
Department of Orthopaedics and Traumatology, Kuopio University Hospital, Kuopio, Finland
69
Center for Clinical and Basic Research (CCBR)-Synarc, Ballerup, Denmark
70
Department of
Nutrition and Dietetics, Harokopio University, Athens, Greece
71
Robertson Center for
Biostatistics, University of Glasgow, Glasgow, United Kingdom
72
Department of Endocrinology,
Odense University Hospital, Odense, Denmark
73
Clinical Institute, University of Southern
Denmark, Odense, Denmark
74
Department of Medicine, McGill University, Montreal, Canada
75
Department of Medicine, University of Cantabria, Santander, Spain
76
Department of Internal
Medicine, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación
Marqués de Valdecilla (IFIMAV), Santander, Spain
77
Department of Clinical Physiology, Tampere
University Hospital, Tampere, Finland
78
Department of Clinical Physiology, University of Tampere
School of Medicine, Tampere, Finland
79
Clinical and Molecular Osteoporosis Research Unit,
Department of Clinical Sciences and Department of Orthopaedics, Lund University, Malmö,
Sweden
80
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada
81
Department of Endocrinology, Vrije Universiteit (VU) University Medical Center, Amsterdam,
The Netherlands
82
Extramuraal Geneeskundig Onderzoek (EMGO) Institute for Health and Care
Research, Vrije Universiteit (VU) University Medical Center, Amsterdam, The Netherlands
83
Department of Medical Sciences, University of Uppsala, Uppsala, Sweden
84
Department of
Pharmacology and Neuroscience, Umeå University, Umeå, Sweden
85
Harvard Medical School,
Boston, USA
86
Department of Molecular Biology, Medical Biochemistry and Pathology, Université
Laval, Québec City, Canada
87
The APOGEE-Net/CanGèneTest Network on Genetic Health
Services and Policy, Université Laval, Québec City, Canada
88
Department of Molecular
Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
89
Department of
Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
90
Li Ka
Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR,
China
91
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
92
Department
of Medicine, Turku University Hospital, Turku, Finland
93
Department of Medicine, University of
Turku, Turku, Finland
94
Department of Legal Medicine, University of Cantabria, Santander, Spain
95
Department of Human Genetics, McGill University, Montreal, Canada
96
McGill University and
Genome Québec Innovation Centre, Montreal, Canada
97
Wellcome Trust Sanger Institute,
Hinxton, UK
98
Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland
99
Institution
of Health Science, University Of Akureyri, Akureyri, Iceland
100
Department of Epidemiology and
Biostatistics, Lady Davis Institute, McGill University, Montreal, Canada
101
Department of Medical
Biochemistry, Oslo University Hospital, Oslo, Norway
102
Medical Genetics Institute, Cedars-Sinai
Medical Center, Los Angeles, USA
103
Department of Endocrinology and Metabolism, University
Hospital, Reykjavik, Iceland
104
Genetics of Complex Traits, Peninsula College of Medicine and
Dentistry, University of Exeter, Exeter, England
105
Department of Clinical Biochemistry,
Lovisenberg Deacon Hospital, Oslo, Norway
106
Institute of Basic Medical Sciences, University of
Oslo, Oslo, Norway
107
Department of Medical Genetics, McGill University Health Centre,
Montreal, Canada
108
Division of Genetics and Rheumatology, Brigham and Women’s Hospital,
Estrada et al.
Page 4
Nat Genet
. Author manuscript; available in PMC 2012 November 01.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Frequently asked questions

Q1. What have the authors contributed in "Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture" ?

The authors 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. The authors report here the results of the largest effort to date searching for BMD loci in > 80,000 subjects and testing them for association with fracture in > 130,000 cases and controls. The authors identified 56 loci ( 32 novel ) associated with BMD atgenome-wide significant level ( P < 5×10−8 ). 

Q2. What future works have the authors mentioned in the paper "Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture" ?

Further exploration of these loci with more detailed sequencing, gene expression, and translational studies will be required. In conclusion, these findings highlight the highly polygenic and complex nature underlying BMD variation, shedding light on the pathophysiological mechanisms underlying fracture susceptibility and harbouring potential for the future identification of drug targets for the treatment of osteoporosis. 

Q3. How many SNPs were removed from the meta-analysis?

45,46 SNPs present in less than three studies were removed from the meta-analysis yielding ~ 2.2 million SNPs in the final results. 

Q4. How many loci were found to be associated with a fracture?

In this fracture meta-analysis fourteen loci were significantly associated with any type of fracture at a Bonferroni level (P=5×10−4), of which five included novel BMD loci. 

Q5. What were the strongest cis-variants in the BMD loci?

Fourteen of the BMD-associated SNPs correlated with the expression of one or more of the nearby genes with P < 5×10−5 and were either the strongest cis-variants, or good surrogates thereof, for those genes (Supplementary Tables 14 and 15). 

Q6. How many SNPs were found in the discovery and replication studies?

The meta-analysis of the 96 SNPs in the discovery and replication studies (n=83,894) yielded 64 replicating SNPs from 56 associated loci. 

Q7. What were the significant SNPs of the X-chromosome?

The 96 variants included the 82 index SNPs representing each of the 82 loci reaching P<5×10−6 in Stage 1, 9 SNPs that lie within the same 2Mb windows as the 82 but which were independent from the main signal (secondary signals), and the top-five most associated SNPs of the X-chromosome (with P <5×10−5). 

Q8. How many additional participants were tested for association with BMD?

The authors de-novo genotyped these 96 SNPs and tested them for association with BMD in up to 50,933 additional participants from 34 studies (see Online Methods). 

Q9. How many individuals of European and East Asian ancestry were included in the meta-analysis?

The authors 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. 

Q10. What was the proportion of the fracture risk explained by FN-BMD?

The proportion of the fracture risk explained by FN-BMD was calculated from the regression coefficients as (βunadjusted - βBMDadjusted)/βunadjusted in a subset of replication samples for which both FNBMD and complete fracture information was available. 

Q11. How do the gradients of risk for osteoporosis and fractures compare?

These gradients reach ORs of 1.56 for osteoporosis and 1.60 for fractures when comparing participants with the highest risk scores with those reflecting the mean score.