Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an 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 4 that putatively modulates the risk of Graves’ disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution.

选择性剪接有助于复杂性状，但尚不清楚这是否在不同遗传祖先的性状相关细胞类型中有所不同。在这里，我们描述了来自亚洲免疫多样性图谱的 474 名健康供体的 ~1 M 外周血单核细胞中的细胞类型特异性、性别偏倚和祖先偏倚的选择性剪接。我们确定了广泛的性别偏倚和祖先偏倚的差异剪接，其中大多数是细胞类型特异性的。我们鉴定了 11,577 个独立的顺式剪接数量性状位点 （sQTL） 、607 个反式基因和 107 个动态 sQTL。cis-eQTLs 和 trans-sQTLs 之间的共定位揭示了 HNRNPLL 和 PTPRC 之间的细胞类型特异性调控关系。我们观察到 cis-sQTL 效应在自身免疫和炎症性疾病遗传性中的富集。具体来说，我们在功能上验证了一种亚洲特异性 sQTL 破坏 TCHP 外显子 4 的 5' 剪接位点，该位点推定调节东亚人群患 Graves 病的风险。我们的工作强调了祖先多样性对剪接的影响，并提供了以单细胞分辨率剖析其在复杂疾病中的作用的路线图。