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

Human molecular genetics ·第 23 卷 ·第 11 期 ·2015-01-12

Moayyeri Alireza, Hsu Yi-Hsiang, Karasik David, Estrada Karol, Xiao Su-Mei, Nielson Carrie, Srikanth Priya, Giroux Sylvie, Wilson Scott G, Zheng Hou-Feng, Smith Albert V, Pye Stephen R, Leo Paul J, Teumer Alexander, Hwang Joo-Yeon, Ohlsson Claes, McGuigan Fiona, Minster Ryan L, Hayward Caroline, Olmos José M, Lyytikäinen Leo-Pekka, Lewis Joshua R, Swart Karin M A, Masi Laura, Oldmeadow Chris, Holliday Elizabeth G, Cheng Sulin, van Schoor Natasja M, Harvey Nicholas C, Kruk Marcin, del Greco M Fabiola, Igl Wilmar, Trummer Olivia, Grigoriou Efi, Luben Robert, Liu Ching-Ti, Zhou Yanhua, Oei Ling, Medina-Gomez Carolina, Zmuda Joseph, Tranah Greg, Brown Suzanne J, Williams Frances M, Soranzo Nicole, Jakobsdottir Johanna, Siggeirsdottir Kristin, Holliday Kate L, Hannemann Anke, Go Min Jin, Garcia Melissa, Polasek Ozren, Laaksonen Marika, Zhu Kun, Enneman Anke W, McEvoy Mark, Peel Roseanne, Sham Pak Chung, Jaworski Maciej, Johansson Åsa, Hicks Andrew A, Pludowski Pawel, Scott Rodney, Dhonukshe-Rutten Rosalie A M, van der Velde Nathalie, Kähönen Mika, Viikari Jorma S, Sievänen Harri, Raitakari Olli T, González-Macías Jesús, Hernández Jose L, Mellström Dan, Ljunggren Osten, Cho Yoon Shin, Völker Uwe, Nauck Matthias, Homuth Georg, Völzke Henry, Haring Robin, Brown Matthew A, McCloskey Eugene, Nicholson Geoffrey C, Eastell Richard, Eisman John A, Jones Graeme, Reid Ian R, Dennison Elaine M, Wark John, Boonen Steven, Vanderschueren Dirk, Wu Frederick C W, Aspelund Thor, Richards J Brent, Bauer Doug, Hofman Albert, Khaw Kay-Tee, Dedoussis George, Obermayer-Pietsch Barbara, Gyllensten Ulf, Pramstaller Peter P, Lorenc Roman S, Cooper Cyrus, Kung Annie Wai Chee, Lips Paul, Alen Markku, Attia John, Brandi Maria Luisa, de Groot Lisette C P G M, Lehtimäki Terho, Riancho José A, Campbell Harry, Liu Yongmei, Harris Tamara B, Akesson Kristina, Karlsson Magnus, Lee Jong-Young, Wallaschofski Henri, Duncan Emma L, O'Neill Terence W, Gudnason Vilmundur, Spector Timothy D, Rousseau François, Orwoll Eric, Cummings Steven R, Wareham Nick J, Rivadeneira Fernando, Uitterlinden Andre G, Prince Richard L, Kiel Douglas P, Reeve Jonathan, Kaptoge Stephen K

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 × 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 × 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 × 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.

文献信息

期刊

Human molecular genetics

期刊简称

Hum Mol Genet

ISSN

0964-6906

发表日期

2015-01-12

收录日期

2014-05-09

更新日期

2016-12-03

语言

英语

国家/地区

England

NLM ID

9208958

外部链接

PubMed 原文查看期刊详情

分析服务

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

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