A polygenic score for height identifies an unmeasured genetic predisposition among pediatric patients with idiopathic short stature

Abstract

Abstract Background A subset of children with short stature do not have an identified clinical explanation after extensive diagnostic evaluation. We hypothesized that a polygenic score for height (PGSheight) could identify children with non-familial idiopathic short stature (ISS-NF) who carry a polygenic predisposition to shorter height that is not accounted for by existing measures. Methods We studied 534 pediatric participants in an electronic health record (EHR)-linked DNA biobank (BioVU) who had been evaluated for short stature by an endocrinologist. Participants were classified as having one of five short stature subtypes: primary growth disorders, secondary growth disorders, idiopathic short stature (ISS), which was sub-classified into familial (ISS-F) and non-familial (ISS-NF), and constitutional delay of puberty (ISS-DP). Differences in polygenic predisposition between subtypes were analyzed using a validated PGSheight which was standardized to a standard deviation score (SDS). Adult height predictions were generated using the PGSheight and mid-parental height (MPH). Within-child differences in height predictions were compared across subtypes. Logistic regression models and AUC analyses were used to test the ability of the PGSheight to differentiate ISS-NF from growth disorders. The incremental improvement (ΔAUC) of adding the PGSheight to prediction models with MPH was also estimated. Results Among the 534 participants, 29.0% had secondary growth disorders, 24.9% had ISS-F, 20.2% had ISS-NF, 17.2% had ISS-DP, and 8.6% had primary growth disorders. Participants with ISS-NF had similar PGSheight values to those with ISS-F (difference [Δ] in PGSheight SDS [95% CI] = 0.19 [− 0.31 to 0.70], p = 0.75). Predicted heights generated by the PGSheight were lower than the MPH estimate for children with ISS-NF (Δ[PGSheight − MPH] = − 0.37 SDS; p = 3.2 × 10−9) but not for children with ISS-F (Δ = − 0.07; p = 0.56). Children with ISS-NF also had lower PGSheight than children with primary growth disorders (ΔPGSheight = − 0.53 [− 1.03 to − 0.04], p = 0.03) and secondary growth disorders (Δ = − 0.45 [− 0.80 to − 0.10], p = 0.005). The PGSheight improved model discrimination between ISS-NF and children with primary (ΔAUC, + 0.07 [95% CI, 0.02 to 0.17]) and secondary growth disorders (ΔAUC, + 0.03 [95% CI, 0.01 to 0.10]). Conclusions Some children with ISS-NF have an unrecognized polygenic predisposition to shorter height, similar to children with ISS-F and greater than those with growth disorders. A PGSheight could aid clinicians in identifying children with a benign, polygenic predisposition to shorter height.

Keywords

• Polygenic scores
• Height
• Common genetic variation
• Short stature
• Idiopathic short stature