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

Journal article
Authors Y. H. Hsu
K. Estrada
E. Evangelou
C. Ackert-Bicknell
K. Akesson
T. Beck
S. J. Brown
T. Capellini
L. Carbone
J. Cauley
C. L. Cheung
S. R. Cummings
S. Czerwinski
S. Demissie
M. Econs
D. Evans
C. Farber
K. Gautvik
T. Harris
C. Kammerer
J. Kemp
D. L. Koller
A. Kung
D. Lawlor
M. Lee
Mattias Lorentzon
F. McGuigan
C. Medina-Gomez
B. Mitchell
A. Newman
C. Nielson
Claes Ohlsson
M. Peacock
S. Reppe
J. B. Richards
J. Robbins
G. Sigurdsson
T. D. Spector
K. Stefansson
E. Streeten
U. Styrkarsdottir
J. Tobias
K. Trajanoska
A. Uitterlinden
Liesbeth Vandenput
S. G. Wilson
L. Yerges-Armstrong
M. Young
M. C. Zillikens
F. Rivadeneira
D. P. Kiel
D. Karasik
Published in Journal of Bone and Mineral Research
Volume 34
Issue 7
Pages 1284-1296
ISSN 0884-0431
Publication year 2019
Published at Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 1284-1296
Language en
Links dx.doi.org/10.1002/jbmr.3698
Keywords 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, Endocrinology & Metabolism, woll es, 1990, journal of clinical endocrinology & metabolism, v70, p1202
Subject categories Clinical Medicine

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 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.

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