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

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.

SUBMITTER: Hsu YH

PROVIDER: S-EPMC6650334 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

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

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20190319 7

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, w ...[more]

PMID: 30888730

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Project description:We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

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

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

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