A polygenic score for height identifies an unmeasured genetic predisposition among pediatric patients with idiopathic short stature
Year: 2024
Type: preprint
Study design: Observational Study
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 (PGSheight) 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 PGSheight and standardized it to a standard deviation (SDS) of 1. PGSheight differences between short stature subtypes was estimated using Tukey’s HSD. The PGSheight 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 PGSheight 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 PGSheight to prediction models. Results Among the 534 participants, 22.1% had ISS (median [IQR] PGSheight 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 PGSheight values as those with FSS (ΔPGSheight [95% CI] = 0.19 [-0.31 to 0.70], p = 0.75), but predicted heights generated by the PGSheight 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 PGSheight values than children with pathology (ΔPGSheight = -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 PGSheight 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 PGSheight could help clinicians identify children who have a benign predisposition to shorter height.
Source: Research Square
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Vanderbilt University, Vanderbilt University Medical Center, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Pharmacogenomics of Arrhythmia Therapy, G1531600799, G1766209448, G2103760183, Understanding the genetic risk underlying racial disparities in uterine fibroids, G2615776415, G2683268942, Vanderbilt Genome-Electronic Records (VGER) Project, Improving Prediction of Drug Action, G3395468139, G3619590958, G364208108, G3791753988, Medical Scientist Training Program, G3938985443, G4049315607, Automated Storage and Retrieval of Biological Systems, G4395870004, G4410787187, BioVU Plasma Storage Equipment, G560889077, G5679716143, G5717004637, Genetic Epidemiology of Multiple Sclerosis, G6246474086, G6589054092, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment, G7163342664, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Vanderbilt Genome Electronic Records Project, G8098630230, Epidemiologic Architecture for Genes Linked to Environment (EAGLE), G8332127685, Leveraging common genetic variation to reduce misclassification of non-diseased individuals and unnecessary health care utilization attributable to surrogate biomarkers, Modular Automated -80C Sample Storage System, Vanderbilt Institute for Clinical and Translational Research (VICTR), Medical Scientist Training Program
OpenAlex ID: W4403404361