Influence of polygenic risk on height and BMI in adults with a 22q11.2 microdeletion

Background Adult height and body mass index (BMI) are highly heritable traits that can be influenced by both common variants, captured collectively in a polygenic risk score (PRS), and by rare variants of large effect. In this study, we aimed to investigate the modifying effect of PRSs for height and BMI in individuals where there is a baseline increased risk for short stature (<3rd percentile height) and obesity (BMI ≥30) conferred by the 22q11.2 microdeletion. Methods Genetic analyses were performed in 259 adults of European ancestry with a typical 22q11.2 microdeletion and available genome sequencing and phenotypic data. We applied published PRSs for height and BMI and tested for association using multivariable linear regression models, adjusting for clinical/demographic variables and 22q11.2 microdeletion extent. Results In multivariable linear regression models, the PRSs for height and BMI were significantly associated (p<0.001) with their respective traits, explaining 25.8% and 5.7% of the variance (ΔR2). The overall models (p<0.001) explained 33.9% and 14.7% of the variance (R2) for height and BMI, respectively. Significant additional covariate predictors of shorter sex-standardized height were longer (LCR22A-D) deletion extent, congenital heart disease, intellectual disability, and the first principal component of ancestry; for BMI, they were female sex and older age. When applying the height-PRS to stratify risk for short stature, we found that significantly more of those in the lowest PRS quintile had short stature, compared to those in the highest quintile (odds ratio=11.46, p=1.74E-05). Using logistic regression models to predict short stature, a receiver operating characteristic curve analysis showed that a model combining height-PRS and clinical/demographic covariates achieved an area of the curve of 0.78, performing significantly better than a covariate-only model. Conclusions The results demonstrate that adult height and BMI can be influenced by the effects of both a 22q11.2 microdeletion and genome-wide common variants. The findings contribute to growing evidence that polygenic risk together with other standard factors can shape adult outcomes of a high-impact rare variant. For height in 22q11.2 microdeletion, PRS may be approaching clinical utility.