Influence of Polygenic Risk on Height and BMI in Adults With a 22q11.2 Microdeletion

Area of Science:

• Genetics
• Human Biology
• Medical Research

Background:

• Elevated a priori risk can increase the clinical utility of polygenic risk scores (PRS).
• The 22q11.2 microdeletion is associated with increased risk for short stature and obesity.

Purpose of the Study:

• To investigate the modifying effect of height and BMI polygenic risk scores (PRS) in individuals with 22q11.2 microdeletion.
• To assess the clinical utility of PRS in refining growth expectations for individuals with elevated baseline genetic risk.

Main Methods:

• Tested height-PRS and BMI-PRS for association with height and BMI in 259 European ancestry adults with 22q11.2 microdeletion.
• Utilized sequencing data and multivariable linear regression models, accounting for clinical/demographic variables.
• Employed logistic regression and receiver operating characteristic curve analysis to predict short stature.

Main Results:

• Height-PRS and BMI-PRS explained 25.8% and 5.7% of trait variance, respectively (P < .001).
• The lowest height-PRS quintile showed a significantly higher prevalence of short stature (42.3%) compared to the highest quintile (5.9%).
• A model combining height-PRS and covariates achieved an AUC of 0.78 for predicting short stature, outperforming a covariate-only model.

Conclusions:

• Genome-wide common variants influence adult height and BMI in individuals with a rare variant conferring elevated a priori risk.
• Height-PRS can help refine growth expectations in individuals with 22q11.2 microdeletion.
• PRS demonstrate potential clinical utility in genetic risk stratification for complex traits.