WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk

被引：250

作者：

Zheng, Hou-Feng ^{[1
,2
]}

Tobias, Jon H. ^{[3
]}

Duncan, Emma ^{[4
,5
]}

Evans, David M. ^{[6
,7
]}

Eriksson, Joel ^{[8
]}

Paternoster, Lavinia ^{[6
,7
]}

Yerges-Armstrong, Laura M. ^{[9
]}

Lehtimaki, Terho ^{[10
,11
]}

Bergstrom, Ulrica

Kahonen, Mika ^{[11
,12
]}

Leo, Paul J. ^{[4
]}

Raitakari, Olli ^{[13
,14
,15
]}

Laaksonen, Marika ^{[16
]}

Nicholson, Geoffrey C. ^{[17
]}

Viikari, Jorma ^{[15
,18
]}

Ladouceur, Martin ^{[19
]}

Lyytikainen, Leo-Pekka ^{[10
,11
]}

Medina-Gomez, Carolina ^{[20
,21
]}

Rivadeneira, Fernando ^{[20
,21
]}

Prince, Richard L. ^{[22
,23
]}

Sievanen, Harri ^{[24
]}

Leslie, William D. ^{[25
]}

Mellstrom, Dan ^{[8
]}

Eisman, John A. ^{[26
]}

Moverare-Skrtic, Sofia ^{[8
]}

Goltzman, David ^{[1
]}

Hanley, David A. ^{[27
]}

Jones, Graeme ^{[28
]}

Pourcain, Beate St. ^{[7
]}

Xiao, Yongjun ^{[29
]}

Timpson, Nicholas J. ^{[6
,7
]}

Smith, George Davey ^{[6
,7
]}

Reid, Ian R. ^{[30
]}

Ring, Susan M. ^{[7
]}

Sambrook, Philip N. ^{[31
]}

Karlsson, Magnus ^{[32
]}

Dennison, Elaine M. ^{[33
]}

Kemp, John P. ^{[7
]}

Danoy, Patrick ^{[4
]}

Sayers, Adrian ^{[3
]}

Wilson, Scott G. ^{[22
,23
,34
]}

Nethander, Maria ^{[35
]}

McCloskey, Eugene ^{[36
,37
]}

Vandenput, Liesbeth ^{[8
]}

Eastell, Richard ^{[36
]}

Liu, Jeff ^{[38
]}

Spector, Tim ^{[34
]}

Mitchell, Braxton D. ^{[9
]}

Streeten, Elizabeth A. ^{[9
,39
]}

Brommage, Robert ^{[38
]}

机构：

[1] McGill Univ, Dept Med, Montreal, PQ, Canada

[2] Jewish Gen Hosp, Lady Davis Inst Med Res, Dept Epidemiol & Biostat, Montreal, PQ, Canada

[3] Univ Bristol, Sch Clin Sci, Musculoskeletal Res Unit, Bristol, Avon, England

[4] Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Human Genet Grp, Brisbane, Qld, Australia

[5] Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia

[6] Univ Bristol, Med Res Council, Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England

[7] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England

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

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

[10] Univ Tampere, Sch Med, Dept Clin Chem, Fimlab, FIN-33101 Tampere, Finland

[11] Tampere Univ Hosp, Tampere, Finland

[12] Univ Tampere, Sch Med, Dept Clin Physiol, FIN-33101 Tampere, Finland

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

[14] Univ Turku, Dept Clin Physiol & Nucl Med, Turku, Finland

[15] Turku Univ Hosp, FIN-20520 Turku, Finland

[16] Univ Helsinki, Dept Food & Environm Sci, Helsinki, Finland

[17] Univ Queensland, Rural Clin Sch, Toowoomba, Qld, Australia

[18] Univ Turku, Dept Med, Turku, Finland

[19] Montreal Heart Inst, Res Inst, Montreal, PQ H1T 1C8, Canada

[20] Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands

[21] Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands

[22] Sir Charles Gairdner Hosp, Perth, WA, Australia

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

[24] UKK Inst, Bone Res Grp, Tampere, Finland

[25] Univ Manitoba, Dept Internal Med, Winnipeg, MB, Canada

[26] Univ New S Wales, Garvan Inst Med Res, Sydney, NSW, Australia

[27] Univ Calgary, Dept Med, Calgary, AB, Canada

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

[29] McGill Univ, Ctr Bone & Periodontal Res, Montreal, PQ, Canada

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

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

[32] Lund Univ, Skane Univ Hosp, Dept Orthopaed, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden

[33] Univ Southampton, Med Res Council, Lifecourse Epidemiol Unit, Southampton, Hants, England

[34] Kings Coll London, London WC2R 2LS, England

[35] Univ Gothenburg, Genom Core Facil, Gothenburg, Sweden

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

[37] Sheffield Teaching Hosp, NIHR Musculoskeletal Biomed Res Unit, Sheffield, S Yorkshire, England

[38] Lexicon Pharmaceut, The Woodlands, TX USA

[39] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr GRECC, Baltimore, MD 21218 USA

[40] Umea Univ, Dept Pharmacol & Neurosci, Umea, Sweden

[41] Umea Unviers, Dept Publ Hlth & Clin Med, Umea, Sweden

来源：

PLOS GENETICS | 2012年 / 8卷 / 07期

基金：

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

关键词：

GENOME-WIDE ASSOCIATION; FREE TESTOSTERONE; GENETIC-FACTORS; HIP-FRACTURES; FEMORAL-NECK; SWEDISH MEN; MASS; BMD; PREDICTOR; GEOMETRY;

D O I：

10.1371/journal.pgen.1002745

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for similar to 2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2x10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3x10(-12), and -0.16 SD per G allele, P = 1.2x10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3x10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9x10(-6) and rs2707466: OR = 1.22, P = 7.2x10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5x10(-13)<P<5.9x10(-4)) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.

引用

页数：13

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