A polygenic risk score identifies undiagnosed cases of diabetes
Authors: German Chris , Ashenhurst James , Wang Wei ,   23andMe Research Team, Granka Julie M. , Koelsch Bertram L. , Abul-Husn Noura S. , Aslibekyan Stella , Auton Adam , Tung Joyce , Shringarpure Suyash S. , Holmes Michael V. 
Published: November 2023

AbstractImportanceTwenty-three percent of 37.3M adults in the USA with diabetes are estimated to be undiagnosed, leading to potentially avoidable sequelae and morbidity.ObjectiveTo explore the utility of a polygenic risk score (PRS) at identifying individuals with undiagnosed diabetes and prediabetes.Design, Setting and ParticipantsIndividuals without doctor-diagnosed diabetes at study baseline in the UK Biobank (UKB) with HbA1c and BMI measurements. Participants were restricted to white individuals to use an ancestry-appropriate PRS. Undiagnosed diabetes and prediabetes were defined using HbA1c (≥6.5% and ≥5.7 - <6.5%, respectively).ExposuresA diabetes PRS comprising 13,863 SNPs derived from the 23andMe Research Cohort, and measured BMI among UKB participants.ResultsOf 412,439 individuals self-reporting an absence of diagnosed diabetes and who had BMI and HbA1c measurements at baseline, 2,934 (0.7%) had undiagnosed diabetes, representing 11.9% of all (diagnosed and undiagnosed) diabetes. Nearly half (1,362, 46%) of undiagnosed diabetes cases were among individuals in the top 25% of the PRS distribution. Overweight individuals (BMI ≥25 - <30 kg/m2) who were in the top 12.5% of the PRS distribution had a similar frequency of undiagnosed diabetes (0.8-1.6% frequency) as individuals with obesity (BMI ≥30kg/m2) in the lowest 12.5% of the PRS distribution (0.7-1.7% frequency). Combining overweight and obesity with the PRS identified nearly all cases of undiagnosed diabetes: individuals with a BMI ≥25 kg/m2(66% of the study population) or those in the top 54-69% of the PRS identified 98-99% of undiagnosed cases. Of the 199 undiagnosed diabetes cases occurring among individuals with a normal BMI (<25kg/m2), two-thirds were among individuals in the top 50% of the PRS. Prediabetes was common (14%), with measured BMI and PRS providing additive risk. Among those in the top 12.5% PRS with BMI ≥35kg/m2, 6.3% developed incident diabetes over 4 years follow-up, as compared to 0% among the bottom 12.5% PRS with BMI<25kg/m2.ConclusionsA diabetes PRS is informative at identifying undiagnosed cases. PRS may have broader utility in detecting individuals with asymptomatic disease.Key PointsQuestionDoes a polygenic risk score (PRS) have utility in identifying individuals with undiagnosed type 2 diabetes (T2D)?FindingsIn this analysis of 412,439 individuals without doctor-diagnosed diabetes, a T2D PRS performed additively to body mass index (BMI) at identifying individuals with undiagnosed diabetes. Selecting individuals on the basis of overweight/obesity or a T2D PRS identified almost all cases of undiagnosed diabetes. The majority of undiagnosed diabetes cases among individuals with normal weight occurred among those at elevated polygenic risk.MeaningA T2D PRS identifies cases of undiagnosed diabetes among individuals with and without overweight or obesity.