Whole-genome Sequencing Association Analysis of Quantitative Platelet Traits in A Large Cohort of β-thalassemia.

Platelet acts as a crucial monitoring indicator for hypercoagulability and thrombosis and a key target for drug regulation. Genotype-phenotype association studies have confirmed that platelet traits are quantitatively regulated by multiple genes. However, there is currently a lack of genetic studies on the heterogeneity of platelet traits in β-thalassemia under hypercoagulable state. Here, we studied the phenotypic heterogeneity of platelet count (PLT) and mean platelet volume (MPV) in 1020 β-thalassemia patients. We further performed a functionally informed whole genome sequencing association analysis of common variants and rare variants (RVs) for PLT and MPV in 916 patients through integrative analysis of whole-genome sequencing data and functional annotation data. Extreme phenotypic heterogeneity of platelet traits was observed in β-thalassemia patients. Additionally, the common variant based gene-level analysis identified the novel gene of RNF144B associated with MPV. The RV analysis identified several novel associations in both coding and noncoding genome, including missense RVs of PPP2R5C associated with PLT and missense RVs of TSSK1B associated with MPV. In conclusion, we performed a comprehensive and systematic whole genome scan of platelet traits in the β-thalassemia cohort, demonstrating the specificity of genetic regulation of platelet traits in the context of β-thalassemia, providing potential targets for intervention.