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

Importance

Twenty-three percent of 37.3M adults in the USA with diabetes are estimated to be undiagnosed, leading to potentially avoidable sequelae and morbidity.

Objective

To explore the utility of a polygenic risk score (PRS) at identifying individuals with undiagnosed diabetes and prediabetes.

Design, Setting and Participants

Individuals 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).

Exposures

A diabetes PRS comprising 13,863 SNPs derived from the 23andMe Research Cohort, and measured BMI among UKB participants.

Results

Of 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.

Conclusions

A diabetes PRS is informative at identifying undiagnosed cases. PRS may have broader utility in detecting individuals with asymptomatic disease.

Key Points

Question

Does a polygenic risk score (PRS) have utility in identifying individuals with undiagnosed type 2 diabetes (T2D)?

Findings

In 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.

Meaning

A T2D PRS identifies cases of undiagnosed diabetes among individuals with and without overweight or obesity.