Development and validation of a Trans-Ancestry polygenic risk score for Type 1 Diabetes

Abstract

Objectives

The high heritability of type 1 diabetes has enabled the development of polygenic risk scores (PRS) as disease risk screening tools. PRS can identify individuals at the highest genetic risk in a population, who can benefit from autoantibody and metabolic surveillance, to avoid ketoacidosis at diagnosis and access preventive therapies. However, PRS for type 1 diabetes developed from European data perform less well in non-European ancestries. We aimed to develop a PRS with comparable performance among different ancestries.

Methods

Using a the PRS-CSx method, and data from large European, East-Asian, African-American and Hispanic type 1 diabetes GWAS (N_{total_cases}=29,469), we developed a trans-ancestry PRS (TA-PS), combining a non-HLA component incorporating over a million variants, with the HLA component of a published European PRS (GRS2x). We tested the performance of the PRS using AUROC, sensitivity and specificity in a multi-ancestry T1D case-control cohort (N_total= 4,657; N_non-European=556) from Montreal, Canada. We validated our results in two independent T1D case-control cohorts (CHOP-CAG and GRACE) and two population-based cohorts (All of Us and UK Biobank).

Results

In our multi-ancestry Montreal-based cohort, TA-PS showed an AUROC of 0.89 which was significantly higher from the AUROC of 0.85 of GRS2x. At a 90th percentile cut-off, in African-Americans, the sensitivity of GRS2x was 0.32, compared to 0.56 in Europeans. For TA-PS, we obtained overall better sensitivities, ranging from 0.71 in Europeans to 0.77 in South Asians. TA-PS demonstrated slightly lower albeit acceptable specificity compared to that of GRS2x (> 0.83 across all ancestries). These results were validated in the four independent cohorts.

Conclusion

We developed a trans-ancestry PRS that outperformed the European-based GRS2x. Importantly, TA-PS provides a comparable prediction in various ancestries, which supports its use in population-wide screening programs

storage of TA-PS