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.

Genomic inbreeding trends, influential sire lines and selection in the global Thoroughbred horse population

“…Here, the selection signal on ECA21 centred on the iroquois homeobox 1 gene (IRX1) and the ADAM metallopeptidase with thrombospondin type 1 motif 16 gene (ADAMTS16), a locus that has been shown to be associated with hip geometry in humans 46 . While ADAMTS16 has been identified among selection signals for high altitude adaptation in pigs 47 , IRX1 is associated with bone mineral density in humans 46 and influences chondrocyte differentiation and may therefore contribute to joint www.nature.com/scientificreports www.nature.com/scientificreports/ flexibility 48 . In horses, genes with functions in bone mineral density have been associated with measurements of joint angles 49 .…”

Osteoporosis: A Long-Term and Late-Effect of Breast Cancer Treatments

“…As such, osteoporosis is a complex genetic disease. There are two to more than five hundred loci associated with bone mineral density (BMD) and fractures [ 14 , 15 ]. There are also single nucleotide polymorphisms (SNPs) associated with AI-induced bone loss or fractures [ 16 , 17 ].…”

Distinct Subsets of Noncoding RNAs Are Strongly Associated With BMD and Fracture, Studied in Weight-Bearing and Non–Weight-Bearing Human Bone

“…To test whether they were associated with hip bone geometry they were correlated to hip structure parameters in n = 80 of the same bone donors. Hip bone geometry in these donors has been described . Interestingly, miR‐16‐1‐3p showed nominally significant correlation with neck shaft angle ( r = −0.22, p = .050) and section modulus of the femoral neck ( r = 0.22, p = .050).…”