Genome Sequencing Unveils a New Regulatory Landscape of Platelet Reactivity

Abstract

Exaggerated platelet aggregation at the site of vascular injury is the underlying pathophysiology of thrombotic diseases. Here, we conduct the largest whole genome sequencing (WGS) effort to uncover the genetic determinants of platelet aggregation. Leveraging 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) individuals deeply phenotyped for platelet aggregation, we identify 18 loci using single-variant approaches. This includes the novel RGS18 locus encoding a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with eQTL signatures for RGS18 expression in platelets. A gene-based approach focusing on deleterious coding variants identifies the SVEP1 gene, previously shown to be associated with coronary artery disease, as a novel determinant of platelet aggregation. Finally, in an integrative approach leveraging epigenetic data on megakaryocytes, we find strong association between rare variants mapping to a super enhancer region for PEAR1. This is a novel finding implicating the importance of rare variants with regulatory potential in a previously documented GWASidentified locus.

Transcriptional profile of platelets and iPSC-derived megakaryocytes from whole-genome and RNA sequencing

“…31 This explains why platelet aggregation is not directly reported in Table 2 despite prior evidence for strong colocalization between the platelet eQTL and the GWAS for platelet aggregation. 32 The other 5 genes whose eQTLs in both platelets and MKs were also reported to have significance in a GWAS were TMEM50A, RHD, RHOF, SERPINE2, and HABP4 (Table 2).…”

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

“…The first set of 53,831 sequenced genomes from TOPMed is now available to the community. The samples are deeply phenotyped and enable discovery of important biology [72][73][74][75][76] for heart, lung, blood, and sleep disorders. In addition, they provide a rich resource for developing and testing methods for surveying human variation, for inference of human demography, and for exploring functional constraint in the genome.…”

High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine

“…Most attention on the potential of DNA sequencing to personalise medicine focuses on discovery of novel genetic causes of disease,[1,43] and development of polygenic risk scores from large-scale studies identifying common variation across blocks of genes co-inherited in linkage disequilibrium[44] that can direct attention to novel cis- regulatory elements. [44,45] The presented approach offers an accelerated route to the clinic, by proceeding from genes already known to have functional impact in processes potentially relevant to the patient.…”

“…Most attention on the potential of DNA sequencing to personalise medicine focuses on discovery of novel genetic causes of disease,[1,43] and development of polygenic risk scores from large-scale studies identifying common variation across blocks of genes co-inherited in linkage disequilibrium[44] that can direct attention to novel cis- regulatory elements. [44,45] The presented approach offers an accelerated route to the clinic, by proceeding from genes already known to have functional impact in processes potentially relevant to the patient. While a small proportion of rare deleterious variants cause recognised human diseases, most do not, either because they are not present at sufficient zygosity, or because they are not in an appropriate patient/environment milieu to be exposed above an essentially compensated perturbation to normal physiology.…”