Leveraging academic medical biobanks for recall-by-genotype deep phenotyping studies

Biobanks have redefined how we study complex diseases, integrating genomic and phenotype data on an unprecedented scale. Population-based biobanks like the UK Biobank have provided powerful tools for epidemiology and polygenic risk stratification, while academic medical biobanks, enriched for advanced and rare diseases, leverage longitudinal electronic health records and deep phenotyping to uncover novel insights into disease mechanisms. A pivotal innovation in this space is the recall-by-genotype (RbG) study design, where individuals are recruited based on genetic variants of interest for detailed (deep) phenotypic investigation. This genome-first approach has enabled groundbreaking studies, from identifying genetic modifiers of rare conditions to leveraging polygenic risk scores for precision medicine. These studies demonstrate the potential of the RbG design to bridge genotype-phenotype relationships and drive biomedical discovery. However, most biobank studies remain underpowered in diverse populations, limiting the research and applicability of these findings. Expanding diversity in biobank datasets is not just a challenge but also an opportunity to make genomic advances equitable and impactful for all. Here, we review the transformative role of RbG studies, explore their application in academic medical biobanks, and discuss their potential to advance the frontier of precision medicine.