Abstract
Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.
Highlights
Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize genome-wide association study (GWAS) potential in the introduction of precision medicine
We found that 87.7% (110,844 of 126,428) of open chromatin regions in MKs fell into four categories (Fig. 1a, Supplementary Fig. 2 for EBs and Supplementary Data 1)
Category II comprised elements that were open throughout differentiation, but were closed in EBs, whereas categories III and IV consisted of elements that opened during the final stage of differentiation, either only in MKs (III) or in both MKs and EBs (IV)
Summary
Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions. Blood cells traits such as counts and mean cellular volumes are highly heritable and can be readily measured using hematology analysers as part of a complete blood count (CBC). By genome-wide association study (GWAS), 2,706 independent sentinel variants associated with 36 CBC-measured traits of blood cells[1]. We provide examples of the effect of common variation on transcriptional mechanisms, which reveal that CBC-P in MK super enhancers (SEs) modify platelet functions
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