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

Elevated a priori risk may enhance the likelihood that common variant effects, captured collectively in a polygenic risk score (PRS), approach clinical utility.

In this study, we investigated the modifying effect of PRSs for adult height and body mass index (BMI) in individuals with elevated baseline risk for short stature (<3rd percentile height) and obesity (BMI ≥30) conferred by a 22q11.2 microdeletion.

We tested height-PRS and BMI-PRS for association with their respective phenotypes in 259 adults of European ancestry with a 22q11.2 microdeletion using sequencing data and multivariable linear regression models to account for clinical/demographic variables.

In multivariable linear regression models, height-PRS and BMI-PRS explained 25.8% and 5.7% of the variance in their respective traits (P < .001 for both). When applying the height-PRS to stratify risk for short stature, 42.3% of individuals in the lowest PRS quintile had short stature (vs 5.9% in the highest PRS quintile, odds ratio = 11.46, P = 1.74E-05). Using logistic regression models to predict short stature in a receiver operating characteristic curve analysis, a model combining height-PRS and clinical/demographic covariates achieved an area under the curve of 0.78, performing significantly better than a covariate-only model.

The results demonstrate that adult height and BMI can be influenced by the effects of genome-wide common variants in the presence of a rare variant conferring elevated a priori risk. Height-PRS may help refine growth expectations in individuals with 22q11.2 microdeletion.