Sex specific genomic insights into type 1 diabetes through GWAS and single cell transcriptome analysis

Type 1 diabetes (T1D) exhibits sex differences in genetic risk, yet most genetic studies treat sex as a covariate rather than a modifier of risk. We hypothesized that sex-stratified genome-wide association studies (GWAS) would uncover sex-specific genetic architecture and improve risk prediction.

We performed GWAS in 6,599 T1D cases (3,483 males, 3,109 females, 7 undetermined) and 12,350 controls (6,665 males, 5,658 females, 27 undetermined) of European ancestry, testing additive models and sex-stratified analyses. For mechanistic insights, we performed scRNA-seq of PBMCs from nine matched male-female pediatric pairs. Finally, we tested male-, female-, and standard polygenic risk scores (PRS) in an independent cohort (471 T1D cases, 2,300 controls).

Sex-stratified analyses identified 215 genome wide significant SNPs (P < 5x10^-8) with heterogeneity: 119 male-specific and 94 female-specific. Integration of scRNA-seq data revealed 41 sex-specific T1D genes with cell type-specific differential expression. In the independent cohort, sex-specific PRS outperformed the combined PRS: in males, AUC = 0.668 versus 0.623 (p < 2.2x10^-16); in females, AUC = 0.719 versus 0.635 (p < 2.2x10^-16).

Sex-stratified GWAS reveal novel T1D risk loci influenced by sex. Incorporating sex-specific effect sizes into PRS enhances risk discrimination, underscoring the value of sex-aware genetic analyses for precise prediction of T1D.