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

Abstract

Background: A subset of children with short stature do not have an identified clinical explanation and are assigned a diagnosis of idiopathic short stature (ISS). We hypothesized that a polygenic score for height (PGS_height) could identify children with ISS who have an unrecognized heritable predisposition to shorter height.

Methods: We examined 534 pediatric participants in an EHR-linked DNA biobank (BioVU) who had undergone an evaluation for short stature by an endocrinologist. We used a previously validated PGS_height and standardized it to a standard deviation (SDS) of 1. PGS_height differences between short stature subtypes was estimated using Tukey's HSD. The PGS_height and mid-parental height (MPH) were then used to predict adult heights for each participant and these predictions were compared using Cohen's d stratifying by short stature subtype. The ability of the PGS_height to discriminate between ISS and short stature due to underlying disease was evaluated using logistic regression models with area under the ROC curve (AUC) analyses and testing the incremental benefit (ΔAUC) of adding the PGS_height to prediction models.

Results: Among the 534 participants, 22.1% had ISS (median [IQR] PGS_height SDS = -1.31 [-2.15 to -0.47]), 6.6% had familial (genetic) short stature (FSS) (-1.62 [-2.13 to -0.54]), and 45.1% had short stature due to underlying pathology (-0.74 [-1.23 to -0.19]). Children with ISS had similar PGS_height values as those with FSS (ΔPGS_height [95% CI] = 0.19 [-0.31 to 0.70], p = 0.75), but predicted heights generated by the PGS_height were lower than the MPH estimate for children with ISS (d = -0.64; p = 4.0×10^-18) but not FSS (d = 0.05; p = 0.46), suggesting that MPH underestimates height in the ISS group. Children with ISS had lower PGS_height values than children with pathology (ΔPGS_height = -0.60 SDS [-0.89 to -0.31], p < 0.001), suggesting children with ISS have a larger predisposition to shorter height. In addition, the PGS_height improved model discrimination between ISS and pathologic short stature (ΔAUC, + 0.07 [95% CI, 0.01 to 0.11]).

Conclusions: Some children with ISS have a clinically unrecognized polygenic predisposition to shorter height that is comparable to children with FSS and larger than those with underlying pathology. A PGS_height could help clinicians identify children who have a benign predisposition to shorter height.

Keywords: Common genetic variation; Height; Idiopathic short stature; Polygenic scores; Short stature.