Development and Validation of a Type 1 Diabetes Multi-Ancestry Polygenic Score

Objective

Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we developed a multi-ancestry polygenic score to accurately predict type 1 diabetes risk across diverse populations.

Research Design and Methods

We used recent multi-ancestry genome-wide association studies to create a type 1 diabetes multi-ancestry polygenic score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores: T1D GRS2_EURand T1D GRS_AFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2_EURand T1D MAPS.

Results

Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2_EUR(0.82,P= 0.04) and T1D GRS_AFR(0.82,P= 0.007). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2_EUR(0.89 vs. 0.91,P= 0.02). However, T1D MAPS2 performed equivalently to T1D GRS2_EURin European ancestry (0.91 vs. 0.91,P= 0.45) while still performing better in non-European ancestry (0.90 vs. 0.82,P= 0.04).

Conclusions

A novel polygenic score improves type 1 diabetes risk prediction in non-European ancestry while maintaining high predictive power in European ancestry. These findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations.

Article Highlights

• Why did we undertake this study?

  Type 1 diabetes polygenic scores are highly predictive of disease risk, but their performance varies based on genetic ancestry.

• What is the specific question(s) we wanted to answer?

  Can we develop a polygenic score that accurately predicts type 1 diabetes risk across diverse populations?

• What did we find?

  Our novel polygenic score performs similarly to existing scores in European populations, and it demonstrates superior performance in non-European populations.

• What are the implications of our findings?

  This polygenic score will improve prediction of type 1 diabetes risk in genetically diverse populations.