Single-cell RNA-seq of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases [scRNAseq_KR_SGI]

Alternative splicing is pivotal in the genetics of complex traits, but a detailed understanding requires relevant cell types from diverse genetic ancestries. Here, we described cell-type-specific, sex-biased, and ancestry-biased alternative splicing in ~1M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identified widespread sex- and ancestry-biased differentially splicing, most of which are cell-type-specific. We identified 11,577 independent cis-sQTLs, 607 trans-sQTLs, and 107 dynamic sQTLs. Colocalization between cis-eQTL and trans-sQTL revealed a cell-type-specific regulatory relationship between hnRNPLL and PTPRC. We observed a strong enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5' splice site of TCHP exon four to putatively modulate the risk of Graves' disease in East Asian populations. Our work highlights the critical impact of ancestral diversity and provides a roadmap to dissect splicing mechanisms in complex diseases at single-cell resolution. Overall design: The raw data contains PBMCs from healthy Asian donors and Caucasians. Asian donors are from Singaporean Chinese, Singaporean Indian, Singaporean Malay, Japanese, and Koreans. Caucasian samples are used as control samples for each batch. Raw genotype and phenotype data associated with this study are available in dbGaP under accession phs003848.v1.p1. Processed expression data is provided in GEO.