OC 68.1 - Platelet RNA-sequencing in 393 Framingham Heart Study participants reveals genetic regulators for a third of expressed transcripts

Background: Expression quantitative trait loci (eQTLs), which designate a variant regulating the expression of a transcript, are often colocalized with GWAS signals and are thus a valuable resource to identify potentially causal genes. However, eQTLs are tissue-specific and the lack of a large-scale platelet eQTL catalog hinders investigations of genetic signals from platelet related traits. The GeneSTAR and CEDAR studies reported platelet-specific eQTLs, but had limited transcripts coverage ( < 6500) and only reported cis-analyses.

Aims: Construct a platelet-specific eQTL catalog from ~400 Framingham Heart Study (FHS) participants.

Methods: Platelet samples were RNA-sequenced and aligned with nf-core using STAR+RSEM quantification. 11,909 transcripts with at least 1 TPM (transcript-per-million) in >20% of samples were selected. Expression levels were normalized using TMM (edgeR library), and eQTL analyses were adjusted on age, sex, aspirin use and relatedness, as well as principal components derived from the genetic and expression matrices. Cis-eQTLs were identified using eigenMT and deemed significant if reaching q-value < 0.05, while significant trans-eQTL were selected if they reached a Bonferroni-defined threshold of P< 4.2E-12 (=5E-8/11,909).

Results: Over a third (N=4,025, 34%) of investigated transcripts were significantly cis-associated, a ratio similar to the GeneSTAR study (36%). These associations explained on average 8.1% of the variance observed for the paired transcript (range: from < 1% to 88%). We also identified trans-associations for 84 transcripts, half of which mapped to one of 10 genetic loci regulating the expression of multiple transcripts (Figure1). For instance, the variant rs1354034 (in ARHGEF3), known to influence platelet count, mean platelet volume as well as platelet activation markers %PAC1 and %CD62P, was associated with the expression of AMD1, HSDL1 and ZNF367 in our study.

Conclusion(s): This analysis resulted in a significant expansion of known, platelet-specific eQTLs, both with cis and trans effects, which will be a valuable resource for future genetic investigations of platelet-related traits.