Leveraging Multi-Ancestry Polygenic Risk Scores for Body Mass Index to Predict Antiretroviral Therapy-Induced Weight Gain*

Widespread availability of antiretroviral therapies (ART) for HIV-1 have generated considerable interest in understanding the pharmacogenomics of ART. In some individuals, ART has been associated with excessive weight gain, which disproportionately affects women of African ancestry. The underlying biology of ART-associated weight gain is poorly understood, but some genetic markers which modify weight gain risk have been suggested, with more genetic factors likely remaining undiscovered. To overcome limitations in available sample sizes for genome-wide association studies (GWAS) in people with HIV, we explored whether a multi-ancestry polygenic risk score (PRS) derived from large, publicly available non-HIV GWAS for body mass index (BMI) can achieve high cross-ancestry performance for predicting baseline BMI in diverse, prospective ART clinical trials datasets, and whether that PRS(BMI) is also associated with change in BMI over 48 weeks on ART. We show that PRS(BMI) explained ~5–7% of variability in baseline (pre-ART) BMI, with high performance in both European and African genetic ancestry groups, but that PRS(BMI) was not associated with change in BMI on ART. This study argues against a shared genetic predisposition for baseline (pre-ART) BMI and ART-associated weight gain.