Loading...
Meta-analysis of genomewide association studies reveals genetic variants for hip bone geometry
Hsu, Yi-Hsiang Estrada, Karol Evangelou, Evangelos Ackert-Bicknell, Cheryl Åkesson, Kristina Beck, Thomas Brown, Suzanne J. Capellini, Terence Carbone, Laura Cauley, Jane
Hsu, Yi-Hsiang
Estrada, Karol
Evangelou, Evangelos
Ackert-Bicknell, Cheryl
Åkesson, Kristina
Beck, Thomas
Brown, Suzanne J.
Capellini, Terence
Carbone, Laura
Cauley, Jane
Author
Hsu, Yi-Hsiang
Estrada, Karol
Evangelou, Evangelos
Ackert-Bicknell, Cheryl
Åkesson, Kristina
Beck, Thomas
Brown, Suzanne J.
Capellini, Terence
Carbone, Laura
Cauley, Jane
Cheung, Ching-Lung
Cummings, Steven R.
Czerwinski, Stefan
Demissie, Serkalem
Econs, Michael J.
Evans, Daniel S.
Farber, Charles
Gautvik, Kaare M.
Harris, Tamara
Kammerer, Candace M.
Kemp, John P.
Koller, Daniel L.
Kung, Annie
Lawlor, Debbie A.
Lee, Miryoung
Lorentzon, Mattias
McGuigan, Fiona
Medina-Gómez, Carolina
Mitchell, Braxton D.
Newman, Anne
Nielson, Carrie
Ohlsson, Claes
Peacock, Munro
Reppe, Sjur
Richards, J. Brent
Robbins, John
Sigurdsson, Gunnar
Spector, Timothy D.
Stefansson, Kari
Streeten, Elizabeth
Styrkarsdottir, Unnur
Tobias, Jonathan
Trajanoska, Katerina
Uitterlinden, André
Vandenput, Liesbeth
Wilson, Scott G.
Yerges-Armstrong, Laura
Young, Mariel
Zillikens, M. Carola
Rivadeneira, Fernando
Kiel, Douglas P.
Karasik, David
Estrada, Karol
Evangelou, Evangelos
Ackert-Bicknell, Cheryl
Åkesson, Kristina
Beck, Thomas
Brown, Suzanne J.
Capellini, Terence
Carbone, Laura
Cauley, Jane
Cheung, Ching-Lung
Cummings, Steven R.
Czerwinski, Stefan
Demissie, Serkalem
Econs, Michael J.
Evans, Daniel S.
Farber, Charles
Gautvik, Kaare M.
Harris, Tamara
Kammerer, Candace M.
Kemp, John P.
Koller, Daniel L.
Kung, Annie
Lawlor, Debbie A.
Lee, Miryoung
Lorentzon, Mattias
McGuigan, Fiona
Medina-Gómez, Carolina
Mitchell, Braxton D.
Newman, Anne
Nielson, Carrie
Ohlsson, Claes
Peacock, Munro
Reppe, Sjur
Richards, J. Brent
Robbins, John
Sigurdsson, Gunnar
Spector, Timothy D.
Stefansson, Kari
Streeten, Elizabeth
Styrkarsdottir, Unnur
Tobias, Jonathan
Trajanoska, Katerina
Uitterlinden, André
Vandenput, Liesbeth
Wilson, Scott G.
Yerges-Armstrong, Laura
Young, Mariel
Zillikens, M. Carola
Rivadeneira, Fernando
Kiel, Douglas P.
Karasik, David
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. © 2019 American Society for Bone and Mineral Research.
Keywords
hip bone geometry, fracture, genomewide association study, meta-analysis, candidate genes, polymorphisms
Date
2019
Type
Journal article
Journal
Journal of Bone and Mineral Research
Book
Volume
34
Issue
7
Page Range
1284-1296
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled