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

Methods 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 both additive and additive-by-sex interaction models. We then conducted GWAS separately in males and females. For mechanistic insights into sex-specific effects, we generated single-cell RNA-sequencing (scRNA-seq) profiles of peripheral blood mononuclear cells (PBMCs) from nine matched male-female pediatric pairs of European ancestry. Finally, we tested male-, female-, and standard (all-samples) polygenic risk scores (PRS) in an independent cohort (471 T1D cases, 2,300 controls), and compared their performance by receiver operating characteristic (ROC) analysis.

Results Sex-stratified analyses identified 215 genome wide significant SNPs (P<5×10-8) exhibiting significant heterogeneity between sexes: 119 male-specific, 94 female-specific, and two shared SNPs at HLA-B (rs2249932 and rs2249934). Integration of scRNA-seq data pinpointed 41 genes with sex-specific T1D associations that also showed differential expression between males and females in particular cell types. In the independent cohort, sex specific PRS significantly outperformed the combined PRS: in males, AUC=0.668 versus 0.623 (Δ=0.045; DeLong’s p<2.2×10-16); in females, AUC=0.719 versus 0.635 (Δ=0.084; DeLong’s p<2.2×10-16).

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

The authors have declared no competing interest.

The study was supported by the Institutional Development Funds from the Children's Hospital of Philadelphia to the Center for Applied Genomics, and The Children's Hospital of Philadelphia Endowed Chair in Genomic Research to HH.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All experimental protocols were approved by the Institutional Review Board (IRB) of the Children's Hospital of Philadelphia (CHOP) with the IRB number: IRB 16-013278. Informed consent was obtained from all subjects. If subjects are under 18, consent was also obtained from a parent and/or legal guardian with assent from the child if 7 years or older.

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The GWAS summary statistics are available from the NHGRI-EBI GWAS Catalog (GCP001356). Scoring files for the male-specific, female-specific, and combined SNP sets will be deposited in the PGS Catalog upon assignment of a DOI for this submission. Their PGS Catalog identifiers will be provided in an update to the medRxiv preprint. Additional information is available from the corresponding author upon request.