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

Hsu, Yi Hsiang; Estrada, Karol; Evangelou, Evangelos; Ackert-Bicknell, Cheryl; Akesson, Kristina LU ; Beck, Thomas; Brown, Suzanne J.; Capellini, Terence; Carbone, Laura and Cauley, Jane, et al. (2019) In Journal of Bone and Mineral Research
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... (More)


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.

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keywords
CANDIDATE GENES, FRACTURE, GENOMEWIDE ASSOCIATION STUDY, HIP BONE GEOMETRY, META-ANALYSIS, POLYMORPHISMS
in
Journal of Bone and Mineral Research
publisher
AMBMR
external identifiers
  • scopus:85063162256
ISSN
0884-0431
DOI
10.1002/jbmr.3698
language
English
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yes
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0fdeb77b-c30c-4644-8564-14ee3a855e1e
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2019-04-05 14:14:43
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2019-04-23 04:48:37
@article{0fdeb77b-c30c-4644-8564-14ee3a855e1e,
  abstract     = {<p><br>
                                                         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                             <br>
                            <sup>–8</sup><br>
                                                         ) 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                             <br>
                            <sup>–5</sup><br>
                                                         ). 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.</p>},
  articleno    = {e3698},
  author       = {Hsu, Yi Hsiang and Estrada, Karol and Evangelou, Evangelos and Ackert-Bicknell, Cheryl and Akesson, Kristina and Beck, Thomas and Brown, Suzanne J. and Capellini, Terence and Carbone, Laura and Cauley, Jane and Cheung, Ching Lung and Cummings, Steven R. and Czerwinski, Stefan and Demissie, Serkalem and Econs, Michael and Evans, Daniel and Farber, Charles and Gautvik, Kaare and Harris, Tamara and Kammerer, Candace and Kemp, John and Koller, Daniel L. and Kung, Annie and Lawlor, Debbie and Lee, Miryoung and Lorentzon, Mattias and McGuigan, Fiona and Medina-Gomez, Carolina and Mitchell, Braxton and Newman, Anne and Nielson, Carrie and Ohlsson, Claes and Peacock, Munro and Reppe, Sjur and Richards, J. Brent and Robbins, John and Sigurdsson, Gunnar and Spector, Timothy D. and Stefansson, Kari and Streeten, Elizabeth and Styrkarsdottir, Unnur and Tobias, Jonathan and Trajanoska, Katerina and Uitterlinden, André and Vandenput, Liesbeth and Wilson, Scott G. and Yerges-Armstrong, Laura and Young, Mariel and Zillikens, Carola and Rivadeneira, Fernando and Kiel, Douglas P. and Karasik, David},
  issn         = {0884-0431},
  keyword      = {CANDIDATE GENES,FRACTURE, GENOMEWIDE ASSOCIATION STUDY,HIP BONE GEOMETRY,META-ANALYSIS,POLYMORPHISMS},
  language     = {eng},
  publisher    = {AMBMR},
  series       = {Journal of Bone and Mineral Research},
  title        = {Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry},
  url          = {http://dx.doi.org/10.1002/jbmr.3698},
  year         = {2019},
}