Key Points

  • iPSC-derived megakaryocytes (MKs) and platelets share eQTLs and show enriched co-location with regulatory tracks important to MK biology.

  • These eQTLs are largely unique to MKs and platelets, with many not seen among 48 tissues in the Genotype-Tissue Expression (GTEx) project

GWAS studies have identified common variants associated with platelet related phenotypes, but because these variants are largely intronic or intergenic, their link to platelet biology is unclear. In 290 normal subjects from the GeneSTAR Research Study (110 African Americans (AAs) and 180 European Americans (EAs)), we generated whole genome sequence data from whole blood and RNA sequence (RNA-seq) data from extracted non-ribosomal RNA from 185 induced pluripotent stem cell-derived megakaryocyte (MK) cell lines (platelet precursor cells) and 290 blood platelet samples from these subjects. Using eigenMT software to select the peak SNP for each expressed gene, and meta-analyzing the results of AAs and EAs, we identify (q-value < 0.05) N=946 cis-expression quantitative trait loci (eQTLs) in derived MKs and N=1,830 cis-eQTLs in blood platelets. Among the 57 eQTLs shared between the two tissues the estimated directions of effect are very consistent (98.2% concordance). A high proportion of detected cis-eQTLs (74.9% in MKs and 84.3% in platelets) are unique to MKs and platelets compared to peak associated SNP-expressed gene pairs of 48 other tissue types that are reported in version V7 of the Genotype-Tissue Expression (GTEx) Project. The locations of our identified eQTLs are significantly enriched for overlap with several annotation tracks highlighting genomic regions with specific functionality in MKs, including MK-specific DNAse hotspots, H3K27-acetylation marks, H3K4-methylation marks, enhancers and super-enhancers. These results offer insights into the regulatory signature of MKs and platelets, with significant overlap in genes expressed, eQTLs detected, and enrichment within known super enhancers relevant to platelet biology.

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