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J Bone Miner Res. 2019 Mar 19:e3698. doi: 10.1002/jbmr.3698. [Epub ahead of print]

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

Author information

1
Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA.
2
Harvard Medical School, Boston, MA.
3
Broad Institute, Cambridge, MA.
4
Department of Internal Medicine, Erasmus MC, 3000 CA, Rotterdam, the Netherlands.
5
Department of Epidemiology, Erasmus MC, 3000 CA, Rotterdam, the Netherlands.
6
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece.
7
Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, New York, USA.
8
Department of Clinical Sciences Malmö, Lund University, Sweden.
9
Department of Orthopedics, Skåne University Hospital, S-205 02, Malmö, Sweden.
10
Beck Radiological Innovations, Baltimore, MD.
11
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia.
12
Department of Human Evolutionary Biology, Harvard University, Cambridge, MA.
13
Department of Medicine at the Medical College of Georgia at Augusta University, Augusta, GA.
14
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
15
Department of Medicine, The University of Hong Kong, Hong Kong, China.
16
California Pacific Medical Center Research Institute, San Francisco, CA.
17
University of Texas, School of Public Health at Bronwsville, TX.
18
Department of Biostatistics, Boston University School of Public Health, Boston, MA.
19
Department of Medicine and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
20
Public Health Sciences, University of Virginia, Charlottesville, VA.
21
Lovisenberg Diakonale Hospital, Unger-Vetlesen Institute, and University of Oslo, Institute of Basic Medical Sciences, Oslo, Norway.
22
Laboratory of Epidemiology and Population Sciences, Intramural Research Program, NIA, Bethesda, MD.
23
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
24
MRC Integrative Epidemiology Unit, University of Bristol, UK.
25
Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
26
Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, and Geriatric Research and Education Clinical Center - Veterans Administration Medical Center, Baltimore, MD.
27
Oregon Health & Science University, Portland, OR.
28
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
29
Oslo University Hospital, Department of Medical Biochemistry, Oslo, Norway.
30
Department of Human Genetics, McGill University, and Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
31
Department of Medicine, University California at Davis, Sacramento, CA.
32
Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
33
Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Campus, London, UK.
34
deCODE Genetics, 101 Reykjavik, Iceland.
35
Musculoskeletal Research Unit, University of Bristol, UK.
36
School of Biomedical Sciences, University of Western Australia, Nedlands, Australia.
37
Genetics, GlaxoSmithKline, King of Prussia, PA.
38
The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.

Abstract

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 ∼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 × 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 × 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.

KEYWORDS:

CANDIDATE GENES; FRACTURE, GENOMEWIDE ASSOCIATION STUDY; HIP BONE GEOMETRY; META-ANALYSIS; POLYMORPHISMS

PMID:
30888730
DOI:
10.1002/jbmr.3698

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