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

Yi Hsiang Hsu, Karol Estrada, Evangelos Evangelou, Cheryl Ackert-Bicknell, Kristina Akesson, Thomas Beck, Suzanne J. Brown, Terence Capellini, Laura Carbone, Jane Cauley, Ching Lung Cheung, Steven R. Cummings, Stefan Czerwinski, Serkalem Demissie, Michael Econs, Daniel Evans, Charles Farber, Kaare Gautvik, Tamara Harris, Candace KammererJohn Kemp, Daniel L. Koller, Annie Kung, Debbie Lawlor, Miryoung Lee, Mattias Lorentzon, Fiona McGuigan, Carolina Medina-Gomez, Braxton Mitchell, Anne Newman, Carrie Nielson, Claes Ohlsson, Munro Peacock, Sjur Reppe, J. Brent Richards, John A Robbins, Gunnar Sigurdsson, Timothy D. Spector, Kari Stefansson, Elizabeth Streeten, Unnur Styrkarsdottir, Jonathan Tobias, Katerina Trajanoska, André Uitterlinden, Liesbeth Vandenput, Scott G. Wilson, Laura Yerges-Armstrong, Mariel Young, Carola Zillikens, Fernando Rivadeneira, Douglas P. Kiel, David Karasik

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Article numbere3698
JournalJournal of Bone and Mineral Research
DOIs
StatePublished - Jan 1 2019

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Hsu, Y. H., Estrada, K., Evangelou, E., Ackert-Bicknell, C., Akesson, K., Beck, T., Brown, S. J., Capellini, T., Carbone, L., Cauley, J., Cheung, C. L., Cummings, S. R., Czerwinski, S., Demissie, S., Econs, M., Evans, D., Farber, C., Gautvik, K., Harris, T., ... Karasik, D. (2019). Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry. Journal of Bone and Mineral Research, [e3698]. https://doi.org/10.1002/jbmr.3698