Polygenic Risk Scores for Islet Autoantibody Positive Early‐Stage Type 1 Diabetes Pre‐Screening

AIMS: To develop a sex-aligned polygenic risk score (PRS) for early-stage type 1 diabetes (T1D) in children without a first-degree family history of T1D. MATERIALS AND METHODS: Global Single Nucleotide Polymorphism (SNP) Array was performed in 16 335 individuals without a first-degree family history of T1D, including 13 956 newborns from the background population of Bavaria, Germany, 240 children with early-stage and 1094 with islet autoantibody-positive Stage 3 T1D from Bavaria as cases and a validation cohort of 695 patients with clinical T1D. Previously developed PRS were assessed and sex-aligned PRS for boys and for girls were developed from 150 SNPs defining 14 HLA DR-DQ haplotypes and 143 T1D genetic susceptibility regions. RESULTS: PRS were similar between children with early-stage T1D and stage 3 T1D for the GPPAD GRS (median 12.8 vs. 12.8, p = 0.81) and the GRS2 (median 13.8 vs. 13.9, p = 0.1). At thresholds corresponding to the 99.2 centile of the background population, the estimated risk for early-stage T1D was higher in boys than girls using both the GPPAD GRS (10.7% in boys vs. 6.8% in girls) and GRS2 (16.4% vs. 8.6%). Novel full (150 SNP) and short (38 SNP) sex-aligned early-stage T1D PRS discriminated cases from controls with around 90% area under the receiver operator characteristic curve in boys and girls. Estimated risks for boys and girls at the 99.2 centile of the background population using the sex-aligned PRS converged, but differences were not eliminated (12.6% for boys, 9.3% for girls). CONCLUSIONS: PRS in children with early-stage and Stage 3 T1D are highly comparable, but suggest a sex bias in early-stage Type 1 diabetes risk in children with high PRS. A sex-aligned PRS was predicted to reduce, but not eliminate, sex-related differences in predicted risk. The PRS was developed primarily in a paediatric population of predominantly European ancestry and requires independent external validation, including in other ancestry groups.