The Polygenic and Monogenic Basis of Paediatric Fractures

Abstract

Purpose of review: Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics.

Recent findings: Large-scale genome-wide studies in children have identified ~44 genetic loci associated with fracture or bone traits whereas ~35 monogenic diseases characterized by paediatric fractures have been described. Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life.

Keywords: Children; Fracture risk; Genetics; Genome-wide association studies; Osteoporosis; Paediatric.

Fig. 1

Differential estimates on bone mineral density (BMD) across the lifespan by age strata. a (i) The A-allele of rs2147161 SNP mapping to RANKL. Data from GWAS for total body bone mineral density (TB BMD). (ii) The C-allele of rs2982562 SNP mapping to ESR1 [17]. b Phenogram of bone-related loci identified by GWAS in the paediatric population, mentioned in this study. The loci are named according to the closest gene, or, a biologically relevant gene within proximity. Loci relate to the following studies: TB BMD, total body BMD [17]; BA, bone accrual [29]; FA BMD, forearm BMD [27]; fracture, paediatric fractures [20]; LL BMD, lower limb BMD [25]; UL BMD, upper limb BMD [25]; SK BMD, skull BMD [25]; FN BMD, femoral neck [31]; LS BMD, lumbar spine [31]; DR BMD, distal radius BMD [31]; pQCT, peripheral quantitative computed tomography [33]