Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

被引：209

作者：

Duncan, Emma L. ^{[1
]}

Danoy, Patrick ^{[1
]}

Kemp, John P. ^{[2
]}

Leo, Paul J. ^{[1
]}

McCloskey, Eugene ^{[3
]}

Nicholson, Geoffrey C. ^{[4
]}

Eastell, Richard ^{[3
]}

Prince, Richard L. ^{[5
,6
]}

Eisman, John A. ^{[7
,8
]}

Jones, Graeme ^{[9
]}

Sambrook, Philip N. ^{[10
]}

Reid, Ian R. ^{[11
]}

Dennison, Elaine M. ^{[12
]}

Wark, John ^{[13
]}

Richards, J. Brent ^{[14
,15
,16
,17
]}

Uitterlinden, Andre G. ^{[18
]}

Spector, Tim D. ^{[17
]}

Esapa, Chris ^{[19
,20
]}

Cox, Roger D. ^{[19
]}

Brown, Steve D. M. ^{[19
]}

Thakker, Rajesh V. ^{[20
]}

Addison, Kathryn A. ^{[1
]}

Bradbury, Linda A. ^{[1
]}

Center, Jacqueline R. ^{[7
,8
]}

Cooper, Cyrus ^{[12
,21
,22
]}

Cremin, Catherine ^{[1
]}

Estrada, Karol ^{[18
]}

Felsenberg, Dieter ^{[23
]}

Glueer, Claus-C. ^{[24
]}

Hadler, Johanna ^{[1
]}

Henry, Margaret J. ^{[25
]}

Hofman, Albert ^{[18
]}

Kotowicz, Mark A. ^{[26
]}

Makovey, Joanna ^{[27
]}

Nguyen, Sing C. ^{[7
,28
]}

Nguyen, Tuan V. ^{[7
,8
,28
]}

Pasco, Julie A. ^{[25
]}

Pryce, Karena ^{[1
]}

Reid, David M. ^{[29
]}

Rivadeneira, Fernando ^{[18
]}

Roux, Christian ^{[30
]}

Stefansson, Kari ^{[31
,32
]}

Styrkarsdottir, Unnur ^{[31
]}

Thorleifsson, Gudmar ^{[31
]}

Tichawangana, Rumbidzai ^{[4
]}

Evans, David M. ^{[2
]}

Brown, Matthew A. ^{[1
,21
,22
]}

机构：

[1] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia

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

[3] Univ Sheffield, Metab Bone Ctr, Acad Unit Bone Metab, Sheffield, S Yorkshire, England

[4] Univ Melbourne, Dept Clin & Biomed Sci, Barwon Hlth, Geelong, Vic, Australia

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

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

[7] Garvan Inst Med Res, Sydney, NSW, Australia

[8] Univ New S Wales, St Vincents Hosp Campus, St Vincents Clin Sch, Sydney, NSW, Australia

[9] Univ Tasmania, Menzies Res Inst, Hobart, Tas, Australia

[10] Univ Sydney, Royal N Shore Hosp, Kolling Inst, Sydney, NSW 2006, Australia

[11] Univ Auckland, Dept Med, Auckland, New Zealand

[12] MRC, Lifecourse Epidemiol Unit, Southampton, Hants, England

[13] Univ Melbourne, Royal Melbourne Hosp, Dept Med & Bone & Mineral Serv, Melbourne, Vic 3050, Australia

[14] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Med, Montreal, PQ H3T 1E2, Canada

[15] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Human Genet, Montreal, PQ H3T 1E2, Canada

[16] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol & Biostat, Montreal, PQ H3T 1E2, Canada

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

[18] Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands

[19] MRC, Mammalian Genet Unit, Harwell, Oxon, England

[20] Univ Oxford, Nuffield Dept Clin Med, Acad Endocrine Unit, Oxford Ctr Diabet Endocrinol & Metab,Churchill Ho, Oxford, England

[21] Univ Oxford, Natl Inst Hlth, Oxford, England

[22] Univ Oxford, Res Biomed Res Unit, Oxford, England

[23] Charite, Free & Humboldt Univ, Ctr Muscle & Bone Res, D-13353 Berlin, Germany

[24] Univ Klinikum Schleswig Holstein, Radiol Diagnost Klin, Kiel, Germany

[25] Deakin Univ, Sch Med, Geelong, Vic 3217, Australia

[26] Barwon Hlth, Dept Endocrinol & Diabet, Geelong, Vic, Australia

[27] Univ Sydney, Inst Bone Joint Res, Royal N Shore Hosp, Sydney, NSW 2006, Australia

[28] Univ New S Wales, Sch Publ Hlth & Community Med, Sydney, NSW, Australia

[29] Univ Aberdeen, Div Appl Med, Aberdeen, Scotland

[30] Paris Descartes Univ, Cochin Hosp, AP HP, Dept Rheumatol, Paris, France

[31] deCODE Genet, Reykjavik, Iceland

[32] Univ Iceland, Reykjavik, Iceland

来源：

PLOS GENETICS | 2011年 / 7卷 / 04期

基金：

加拿大健康研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

FAMILIAL TUMORAL CALCINOSIS; KLOTHO GENE; LARGE-SCALE; GENDER SPECIFICITY; DETERMINANTS; WOMEN; POLYMORPHISMS; OSTEOPOROSIS; MASS; PREVALENCE;

D O I：

10.1371/journal.pgen.1001372

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age- specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender- adjusted BMD zscores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.

引用

页数：10

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