A combined polygenic score of 21,293 rare and 22 common variants improves diabetes diagnosis based on hemoglobin A1C levels

Polygenic scores (PGSs) combine the effects of common genetic variants^1,2 to predict risk or treatment strategies for complex diseases^3–7. Adding rare variation to PGSs has largely unknown benefits and is methodically challenging. Here, we developed a method for constructing rare variant PGSs and applied it to calculate genetically modified hemoglobin A1C thresholds for type 2 diabetes (T2D) diagnosis^7–10. The resultant rare variant PGS is highly polygenic (21,293 variants across 154 genes), depends on ultra-rare variants (72.7% observed in fewer than three people) and identifies significantly more undiagnosed T2D cases than expected by chance (odds ratio = 2.71; P = 1.51 × 10⁻⁶). A PGS combining common and rare variants is expected to identify 4.9 million misdiagnosed T2D cases in the United States—nearly 1.5-fold more than the common variant PGS alone. These results provide a method for constructing complex trait PGSs from rare variants and suggest that rare variants will augment common variants in precision medicine approaches for common disease.