Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

被引：83

作者：

Moayyeri, Alireza ^{[1
,2
]}

Hsu, Yi-Hsiang ^{[3
,4
,5
]}

Karasik, David ^{[3
,4
,5
]}

Estrada, Karol ^{[6
,7
,8
,9
,10
]}

Xiao, Su-Mei ^{[11
,12
]}

Nielson, Carrie ^{[15
]}

Srikanth, Priya ^{[15
]}

Giroux, Sylvie ^{[17
]}

Wilson, Scott G. ^{[2
,18
,19
]}

Zheng, Hou-Feng ^{[20
,21
,22
,23
]}

Smith, Albert V. ^{[24
,25
]}

Pye, Stephen R. ^{[26
]}

Leo, Paul J. ^{[28
]}

Teumer, Alexander ^{[29
]}

Hwang, Joo-Yeon ^{[33
]}

Ohlsson, Claes ^{[34
]}

McGuigan, Fiona ^{[35
]}

Minster, Ryan L. ^{[37
]}

Hayward, Caroline ^{[39
]}

Olmos, Jose M. ^{[40
,41
,42
]}

Lyytikaeinen, Leo-Pekka ^{[43
,44
]}

Lewis, Joshua R. ^{[18
,19
]}

Swart, Karin M. A. ^{[46
]}

Masi, Laura ^{[49
]}

Oldmeadow, Chris ^{[51
,52
]}

Holliday, Elizabeth G. ^{[51
,52
]}

Cheng, Sulin ^{[53
]}

van Schoor, Natasja M. ^{[46
]}

Harvey, Nicholas C. ^{[54
]}

Kruk, Marcin ^{[55
]}

Fabiola Del Greco, M. ^{[56
,57
]}

Igl, Wilmar ^{[58
]}

Trummer, Olivia ^{[60
]}

Grigoriou, Efi ^{[61
]}

Luben, Robert ^{[1
]}

Liu, Ching-Ti ^{[62
]}

Zhou, Yanhua ^{[62
]}

Oei, Ling ^{[6
,7
,10
]}

Medina-Gomez, Carolina ^{[6
,7
,10
]}

Zmuda, Joseph ^{[38
]}

Tranah, Greg ^{[63
,64
]}

Brown, Suzanne J. ^{[19
]}

Williams, Frances M. ^{[2
]}

Soranzo, Nicole ^{[65
]}

Jakobsdottir, Johanna ^{[24
]}

Siggeirsdottir, Kristin ^{[24
,25
]}

Holliday, Kate L. ^{[26
]}

Hannemann, Anke ^{[30
,31
]}

Go, Min Jin ^{[33
]}

Garcia, Melissa ^{[66
]}

机构：

[1] Univ Cambridge, Dept Publ Hlth Primary Care, Cambridge CB1 8RN, England

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

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

[4] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[5] Harvard Univ, Sch Med, Boston, MA USA

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

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

[8] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit,Dept Med, Boston, MA USA

[9] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[10] Netherlands Consortium Healthy Aging NCHA, Netherlands Genom Initiat NGI, Leiden, Netherlands

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

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

[13] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China

[14] Univ Hong Kong, Ctr Reprod Dev & Growth, Hong Kong, Hong Kong, Peoples R China

[15] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA

[16] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97201 USA

[17] HSFA, Ctr Rech CHU Quebec, Quebec City, PQ, Canada

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

[19] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Perth, WA 6000, Australia

[20] McGill Univ, Lady Davis Inst, Dept Med, Montreal, PQ, Canada

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

[22] McGill Univ, Lady Davis Inst, Dept Epidemiol, Montreal, PQ, Canada

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

[24] Iceland Heart Assoc, Kopavogur, Iceland

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

[26] Univ Manchester, Manchester Royal Infirm, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Epidemiol Unit, Manchester M13 9WL, Lancs, England

[27] Univ Manchester, Manchester Royal Infirm, Manchester Acad Hlth Sci Ctr, Androl Res Unit,Dev & Regenerat Biomed Res Grp, Manchester M13 9WL, Lancs, England

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

[29] Ernst Moritz Arndt Univ Greifswald, Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany

[30] Ernst Moritz Arndt Univ Greifswald, Univ Med Greifswald, Inst Clin Chem, Greifswald, Germany

[31] Ernst Moritz Arndt Univ Greifswald, Univ Med Greifswald, Lab Med, Greifswald, Germany

[32] Ernst Moritz Arndt Univ Greifswald, Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[33] NIH, Ctr Genome Sci, Chungcheongbuk, South Korea

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

[35] Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci, Malmo, Sweden

[36] Lund Univ, Dept Orthopaed, Malmo, Sweden

[37] Univ Pittsburgh, Dept Human Genet, Pitsburgh, PA USA

[38] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pitsburgh, PA USA

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

[40] Univ Cantabria, Dept Med, E-39005 Santander, Spain

[41] Hosp Univ Marques Valdecilla, Dept Internal Med, Santander, Spain

[42] Inst Formac & Invest Marques Valdecilla IFIMAV, Santander, Spain

[43] Fimlab Labs, Dept Clin Chem, Tampere, Finland

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

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

[46] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands

[47] Vrije Univ Amsterdam, Med Ctr, Dept Endocrinol, Amsterdam, Netherlands

[48] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands

[49] Univ Florence, Metab Bone Dis Unit AOUC, Florence, Italy

[50] Univ Florence, Dept Surg & Translat Med, Florence, Italy

来源：

HUMAN MOLECULAR GENETICS | 2014年 / 23卷 / 11期

关键词：

X-RAY ABSORPTIOMETRY; QUANTITATIVE ULTRASOUND; MINERAL DENSITY; OSTEOPOROSIS; FRACTURES; RISK; DENSITOMETRY; PHENOTYPES; CALCANEUS; WOMEN;

D O I：

10.1093/hmg/ddt675

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

引用

页码：3054 / 3068

页数：15

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