Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry

被引：28

作者：

Hsu, Yi-Hsiang ^{[1
,2
,3
]}

Estrada, Karol ^{[3
,4
,5
]}

Evangelou, Evangelos ^{[6
]}

Ackert-Bicknell, Cheryl ^{[7
]}

Akesson, Kristina ^{[8
,9
]}

Beck, Thomas ^{[10
]}

Brown, Suzanne J. ^{[11
]}

Capellini, Terence ^{[12
]}

Carbone, Laura ^{[13
]}

Cauley, Jane ^{[14
]}

Cheung, Ching-Lung ^{[15
]}

Cummings, Steven R. ^{[16
]}

Czerwinski, Stefan ^{[17
]}

Demissie, Serkalem ^{[18
]}

Econs, Michael ^{[19
,20
]}

Evans, Daniel ^{[16
]}

Farber, Charles ^{[21
]}

Gautvik, Kaare ^{[22
,23
]}

Harris, Tamara ^{[24
]}

Kammerer, Candace ^{[14
]}

Kemp, John ^{[25
,26
]}

Koller, Daniel L. ^{[19
,20
]}

Kung, Annie ^{[15
]}

Lawlor, Debbie ^{[26
]}

Lee, Miryoung ^{[17
]}

Lorentzon, Mattias ^{[27
]}

McGuigan, Fiona ^{[7
,8
]}

Medina-Gomez, Carolina ^{[5
]}

Mitchell, Braxton ^{[28
,29
,30
]}

Newman, Anne ^{[14
]}

Nielson, Carrie ^{[31
]}

Ohlsson, Claes ^{[32
]}

Peacock, Munro ^{[19
,20
]}

Reppe, Sjur ^{[22
,23
,33
]}

Richards, J. Brent ^{[34
,35
]}

Robbins, John ^{[36
]}

Sigurdsson, Gunnar ^{[37
]}

Spector, Timothy D. ^{[38
]}

Stefansson, Kari ^{[39
]}

Streeten, Elizabeth ^{[28
,29
,30
]}

Styrkarsdottir, Unnur ^{[39
]}

Tobias, Jonathan ^{[40
]}

Trajanoska, Katerina ^{[5
]}

Uitterlinden, Andre ^{[4
,5
]}

Vandenput, Liesbeth ^{[32
]}

Wilson, Scott G. ^{[11
,38
,41
]}

Yerges-Armstrong, Laura ^{[42
]}

Young, Mariel ^{[12
]}

Zillikens, M. Carola ^{[4
,5
]}

Rivadeneira, Fernando ^{[4
,5
]}

机构：

[1] Hebrew SeniorLife, Hinda & Arthur Marcus Inst Aging Res, Boston, MA USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Broad Inst, Cambridge, MA USA

[4] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands

[5] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands

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

[7] Univ Rochester, Dept Orthopaed, Ctr Musculoskeletal Res, Rochester, NY USA

[8] Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden

[9] Skane Univ Hosp, Dept Orthoped, S-20502 Malmo, Sweden

[10] Beck Radiol Innovat, Baltimore, MD USA

[11] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA, Australia

[12] Harvard Univ, Dept Human Evolutionary Biol, Cambridge, MA 02138 USA

[13] Augusta Univ, Med Coll Georgia, Dept Med, Augusta, GA USA

[14] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA

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

[16] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA

[17] Univ Texas Brownsville, Sch Publ Hlth Bronwsville, Brownsville, TX 78520 USA

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

[19] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA

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

[21] Univ Virginia, Publ Hlth Sci, Charlottesville, VA USA

[22] Lovisenberg Diakonale Hosp, Unger Vetlesen Inst, Oslo, Norway

[23] Univ Oslo, Inst Basic Med Sci, Oslo, Norway

[24] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA

[25] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia

[26] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England

[27] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med, SE-41345 Gothenburg, Sweden

[28] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA

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

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

[31] Oregon Hlth & Sci Univ, Portland, OR 97201 USA

[32] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med & Clin Nutr, SE-41345 Gothenburg, Sweden

[33] Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway

[34] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[35] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ, Canada

[36] Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA

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

[38] Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus, London, England

[39] deCODE Genet, IS-101 Reykjavik, Iceland

[40] Univ Bristol, Musculoskeletal Res Unit, Bristol, Avon, England

[41] Univ Western Australia, Sch Biomed Sci, Nedlands, WA, Australia

[42] GlaxoSmithKline, Genet, King Of Prussia, PA USA

[43] Bar Ilan Univ, Azrieli Fac Med, IL-1311502 Safed, Israel

来源：

JOURNAL OF BONE AND MINERAL RESEARCH | 2019年 / 34卷 / 07期

基金：

以色列科学基金会; 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; 瑞典研究理事会;

关键词：

HIP BONE GEOMETRY; FRACTURE; GENOMEWIDE ASSOCIATION STUDY; META-ANALYSIS; CANDIDATE GENES; POLYMORPHISMS; LD SCORE REGRESSION; MINERAL DENSITY; WIDE ASSOCIATION; VERTEBRAL FRACTURES; AXIS LENGTH; RISK; MEN; HERITABILITY; OSTEOPOROSIS; VARIABLES;

D O I：

10.1002/jbmr.3698

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with similar to 2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p <= 2.6 x 10(-8)) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 x 10(-5)). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. (c) 2019 American Society for Bone and Mineral Research.

引用

页码：1284 / 1296

页数：13

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