Genetic associations between asthma and type 2 inflammatory diseases: Insights from pleiotropic loci and genes: shared genetics of Type 2 Iinflammatory diseases: Shared Genetics of Type 2 Inflammatory Diseases.

BACKGROUND

Type 2 inflammatory diseases (T2IDs) often coexist, but their shared genetic basis remains unclear. This study explores common genetic basis between asthma and other T2IDs and identifies pleiotropic loci and mechanisms.

METHODS

Using genome-wide association study (GWAS) summary statistics, we assessed genetic correlation between asthma and four T2IDs (allergic conjunctivitis [AC], allergic rhinitis [AR], pollen allergy [PA], atopic dermatitis [AD]) via cross-trait pleiotropy analysis, followed by functional, tissue-specificity, and multi-trait colocalization analyses.

RESULTS

Significant genetic correlations were detected in all four trait pairs. Pleiotropy analysis under the composite null hypothesis (PLACO) identified 21 pleiotropic loci, with 2 colocalized (PP.H4 > 0.75). Notable pleiotropic loci were identified, such as 4q24 (MANBA, UBE2D3, and CISD2) and 19q13.2 (SNRPA, RAB4B, MIA-RAB4B, and EGLN). MAGMA revealed 49 candidate pleiotropic genes involved in synaptic structure/function and cellular organization. Tissue enrichment analysis, stratified LD score regression (S-LDSC), and summary data-based Mendelian randomization (SMR) analysis revealed that pleiotropic mechanisms play significant roles in the brain, spleen, whole blood, and EBV-transformed lymphocytes. Hyprcoloc implicated distinct lymphocyte subtypes in shared mechanisms between asthma and AD.

CONCLUSIONS

We identified shared genetic loci and gene sets between asthma and T2IDs, offering insights into genetic mechanisms and potential therapeutic targets.