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

被引：909

作者：

Estrada, Karol ^{[1
,2
,3
]}

Styrkarsdottir, Unnur ^{[4
]}

Evangelou, Evangelos ^{[5
]}

Hsu, Yi-Hsiang ^{[6
,7
]}

Duncan, Emma L. ^{[8
,9
]}

Ntzani, Evangelia E. ^{[5
]}

Oei, Ling ^{[1
,2
,3
]}

Albagha, Omar M. E. ^{[10
]}

Amin, Najaf ^{[2
]}

Kemp, John P. ^{[11
]}

Koller, Daniel L. ^{[12
]}

Li, Guo ^{[13
]}

Liu, Ching-Ti ^{[14
]}

Minster, Ryan L. ^{[15
]}

Moayyeri, Alireza ^{[16
,17
]}

Vandenput, Liesbeth ^{[18
]}

Willner, Dana ^{[8
,19
]}

Xiao, Su-Mei ^{[20
,21
]}

Yerges-Armstrong, Laura M. ^{[22
]}

Zheng, Hou-Feng ^{[23
]}

Alonso, Nerea ^{[10
]}

Eriksson, Joel ^{[18
]}

Kammerer, Candace M. ^{[15
]}

Kaptoge, Stephen K. ^{[16
]}

Leo, Paul J. ^{[8
]}

Thorleifsson, Gudmar ^{[4
]}

Wilson, Scott G. ^{[17
,24
,25
]}

Wilson, James F. ^{[26
,27
]}

Aalto, Ville ^{[28
,29
]}

Alen, Markku ^{[30
,31
]}

Aragaki, Aaron K. ^{[32
]}

Aspelund, Thor ^{[33
,34
]}

Center, Jacqueline R. ^{[35
,37
]}

Dailiana, Zoe ^{[38
]}

Duggan, David J. ^{[39
]}

Garcia, Melissa ^{[40
]}

Garcia-Giralt, Natalia ^{[41
]}

Giroux, Sylvie ^{[42
]}

Hallmans, Goran ^{[43
]}

Hocking, Lynne J. ^{[44
]}

Husted, Lise Bjerre ^{[45
]}

Jameson, Karen A. ^{[46
]}

Khusainova, Rita ^{[47
,48
]}

Kim, Ghi Su ^{[49
]}

Kooperberg, Charles ^{[32
]}

Koromila, Theodora ^{[50
]}

Kruk, Marcin ^{[51
]}

Laaksonen, Marika ^{[52
]}

Lacroix, Andrea Z. ^{[32
]}

Lee, Seung Hun ^{[49
]}

机构：

[1] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[2] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[3] Netherlands Genom Initiat NGI Sponsored Netherlan, Leiden, Netherlands

[4] deCODE Genet, Reykjavik, Iceland

[5] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece

[6] Hebrew SeniorLife, Inst Aging Res, Boston, MA USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[8] Univ Queensland, Diamantina Inst, Human Genet Grp, Brisbane, Qld, Australia

[9] Royal Brisbane & Womens Hosp, Dept Endocrinol, Brisbane, Qld, Australia

[10] Univ Edinburgh, Rheumat Dis Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[11] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England

[12] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[13] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[14] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[15] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA

[16] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[17] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[18] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden

[19] Univ Queensland, Australian Ctr Ecogenom, Brisbane, Qld, Australia

[20] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China

[21] Univ Hong Kong, Res Ctr Heart Brain Hormone & Hlth Aging, Hong Kong, Hong Kong, Peoples R China

[22] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[23] McGill Univ, Dept Human Genet, Lady Davis Inst, Montreal, PQ, Canada

[24] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia

[25] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Perth, WA, Australia

[26] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[27] Univ Edinburgh, MRC Human Genet Unit, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[28] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland

[29] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland

[30] Oulu Univ Hosp, Dept Med Rehabil, Oulu, Finland

[31] Inst Hlth Sci, Oulu, Finland

[32] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA

[33] Iceland Heart Assoc, Kopavogur, Iceland

[34] Univ Iceland, Fac Med, Reykjavik, Iceland

[35] Garvan Inst Med Res, Osteoporosis & Bone Biol Program, Sydney, NSW, Australia

[36] Univ New S Wales, Dept Med, Sydney, NSW, Australia

[37] St Vincents Hosp, Dept Endocrinol, Sydney, NSW 2010, Australia

[38] Univ Thessalia, Sch Med, Dept Orthopaed Surg, Larisa, Greece

[39] Translat Genom Res Inst, Phoenix, AZ USA

[40] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA

[41] Univ Autonoma Barcelona, Red Lemat Invest Cooperat Envejecimiento & Fragil, Dept Internal Med, Hosp Mar,IMIM, E-08193 Barcelona, Spain

[42] CHUQ HSFA, Unite Rech Genet Humaine & Mol, Ctr Rech, Quebec City, PQ, Canada

[43] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden

[44] Univ Aberdeen, Musculoskeletal Res Programme, Div Appl Med, Aberdeen, Scotland

[45] Aarhus Univ Hosp, Dept Endocrinol & Internal Med, Aarhus C, Denmark

[46] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England

[47] Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa 450001, Russia

[48] Bashkir State Univ, Dept Biol, Ufa 450074, Russia

[49] Univ Ulsan, Coll Med, Asan Med Ctr, Div Endocrinol & Metab, Seoul, South Korea

[50] Univ Athens, Fac Biol, Dept Genet & Biotechnol, Athens, Greece

来源：

NATURE GENETICS | 2012年 / 44卷 / 05期

基金：

芬兰科学院; 英国医学研究理事会; 美国国家卫生研究院; 瑞典研究理事会; 加拿大健康研究院; 英国惠康基金;

关键词：

OSTEOPOROTIC FRACTURES; GENE; VARIANTS; LRP5; EXPRESSION; PATTERNS; DISEASE; BURDEN; WOMEN; HIP;

D O I：

10.1038/ng.2249

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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 x 10(-4), Bonferroni corrected), of which six reached P < 5 x 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.

引用

页码：491 / +

页数：13

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