Sex-aligned genetic scores narrow predicted early-stage type 1 diabetes risk differences

Researchers developed sex-aligned polygenic risk scores (PRS) to support early-stage type 1 diabetes pre-screening in children without a first-degree family history. The observational study included 16,335 individuals: 13,956 newborns from Bavaria’s background population, 240 children with early-stage disease, 1,094 with islet autoantibody-positive stage 3 disease, and a validation cohort of 695 patients with clinical type 1 diabetes. Analyses assessed existing scores and developed new scores incorporating sex.

Existing PRS were similar in early-stage and stage 3 disease: median GPPAD GRS values were 12.8 versus 12.8, and GRS2 values were 13.8 versus 13.9. However, at thresholds corresponding to the background population’s 99.2nd percentile, estimated early-stage disease risk was higher in boys than girls: 10.7% versus 6.8% with GPPAD GRS and 16.4% versus 8.6% with GRS2.

New 150-SNP and 38-SNP sex-aligned scores discriminated cases from controls with approximately 90% area under the receiver operating characteristic curve in both sexes. Estimated risks at the 99.2nd percentile became closer but remained different: 12.6% in boys and 9.3% in girls. These findings suggest potential for more balanced genetic pre-screening, rather than demonstrating improved clinical outcomes. Development was primarily in children of predominantly European ancestry; independent external validation, including other ancestry groups, remains necessary.