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

Area of Science:

• Genetics
• Immunology
• Endocrinology

Background:

• Type 1 diabetes (T1D) presents with known sex differences in genetic risk.
• Current genetic studies often overlook sex as a critical modifier of risk, treating it merely as a covariate.
• This approach may limit the discovery of specific genetic factors and the accuracy of risk prediction.

Purpose of the Study:

• To investigate the hypothesis that sex-stratified genome-wide association studies (GWAS) can identify sex-specific genetic architecture in T1D.
• To determine if sex-specific genetic analyses can enhance the prediction of T1D risk.

Main Methods:

• Conducted GWAS in a large cohort of T1D cases and controls of European ancestry, performing both standard and sex-stratified analyses.
• Utilized single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from matched male-female pediatric pairs to explore mechanistic insights.
• Validated findings by testing male-specific, female-specific, and standard polygenic risk scores (PRS) in an independent cohort.

Main Results:

• Sex-stratified GWAS identified 215 genome-wide significant single nucleotide polymorphisms (SNPs), with 119 showing male-specific and 94 showing female-specific associations.
• Integration with scRNA-seq data revealed 41 T1D genes with sex-specific and cell type-specific differential expression patterns.
• In an independent cohort, sex-specific PRS demonstrated superior predictive performance over combined PRS for both males (AUC 0.668 vs. 0.623) and females (AUC 0.719 vs. 0.635).

Conclusions:

• Sex-stratified GWAS analyses are crucial for uncovering novel T1D risk loci that are influenced by sex.
• Incorporating sex-specific genetic effect sizes into PRS significantly improves risk discrimination for T1D.
• These findings highlight the importance of sex-aware genetic analyses for achieving precise T1D risk prediction.