RESUMEN
BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
Asunto(s)
Cromosomas Humanos Par 6/genética , Osteoporosis/genética , Fracturas Osteoporóticas/genética , Estudios de Casos y Controles , Puntos de Rotura del Cromosoma , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Eliminación de Gen , Dosificación de Gen , Estudio de Asociación del Genoma Completo , Humanos , Cadenas de Markov , Persona de Mediana EdadRESUMEN
Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (nâ=â1,397) and two Chinese Hong Kong sample sets (nâ=â3,869 and nâ=â785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, Pâ=â4.3×10(-9)), 1p31 (GPR177, Pâ=â0.00012), 3p22 (CTNNB1, Pâ=â0.00013), 4q22 (MEPE, Pâ=â0.0026), 5q14 (MEF2C, Pâ=â1.3×10(-5)), 6q25 (ESR1, Pâ=â0.0011), 7p14 (STARD3NL, Pâ=â0.00025), 7q21 (FLJ42280, Pâ=â0.00017), 8q24 (TNFRSF11B, Pâ=â3.4×10(-5)), 11p15 (SOX6, Pâ=â0.00033), 11q13 (LRP5, Pâ=â0.0033), 13q14 (TNFSF11, Pâ=â7.5×10(-5)), 16q24 (FOXL1, Pâ=â0.0010) and 17q21 (SOST, Pâ=â0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.