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Chunk #15 — Results — One third of trait-associated variants have distal effects

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Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.
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Compared to bulk datasets, scRNA-seq eQTL datasets are less impacted by cell-composition and are therefore ideal for trans-eQTL replication. We performed replication analyses in B-cells, CD4+ T-cells, CD8+ T-cells, classical monocytes, non-classical monocytes, dendritic cells, natural killer (NK) cells and plasma cells from up to 1,139 individuals (OneK1K, N=982 and 1M-scBloodNL, N=157; Supplementary Note). Depending on the cell type, we could reliably test between 1,917 and 27,582 discovery trans-eQTLs (Figure 3a) and replicated 35 trans-eQTLs at FDR<0.05 (Supplementary Table 4), with two effects replicating in more than one cell type. For those trans-eQTLs, the allelic concordance between the discovery and the replication analysis was 97%. For 7 out of the 8 cell types, we observed inflation of replication signal (Supplementary Table 5, Supplementary Figure 6a) and greater than expected allelic concordance with the discovery analysis (Figure 3a; Supplementary Table 5; two-sided binomial test P<0.05). Similarly, trans-eQTL effect sizes correlated significantly with replication effects in the scRNA-seq data (rb metric24; Methods, Figure 3a; two-sided P<0.05) for 4 cell types (classical monocytes (P=3.36×10−8, rb=0.514, S.E.=0.093), NK cells (P=3.24×10−4, rb=0.185, S.E.=0.051), CD8+ lymphocytes