title: Integrative Multi-omic Analysis of Human Platelet eQTLs Reveals Alternative Start Site in Mitofusin 2.
abstract: Platelets play a central role in ischemic cardiovascular events. Cardiovascular disease (CVD) is a major cause of death worldwide. Numerous genome-wide association studies (GWASs) have identified loci associated with CVD risk. However, our understanding of how these variants contribute to disease is limited. Using data from the platelet RNA and expression 1 (PRAX1) study, we analyzed cis expression quantitative trait loci (eQTLs) in platelets from 154 normal human subjects. We confirmed these results in silico by performing allele-specific expression (ASE) analysis, which demonstrated that the allelic directionality of eQTLs and ASE patterns correlate significantly. Comparison of platelet eQTLs with data from the Genotype-Tissue Expression (GTEx) project revealed that a number of platelet eQTLs are platelet specific and that platelet eQTL peaks localize to the gene body at a higher rate than eQTLs from other tissues. Upon integration with data from previously published GWASs, we found that the trait-associated variant rs1474868 coincides with the eQTL peak for mitofusin 2 (MFN2). Additional experimental and computational analyses revealed that this eQTL is linked to an unannotated alternate MFN2 start site preferentially expressed in platelets. Integration of phenotype data from the PRAX1 study showed that MFN2 expression levels were significantly associated with platelet count. This study links the variant rs1474868 to a platelet-specific regulatory role for MFN2 and demonstrates the utility of integrating multi-omic data with eQTL analysis in disease-relevant tissues for interpreting GWAS results.
authors.affiliation: Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lukas M
authors.initials: LM
authors.lastname: Simon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Chen
authors.affiliation: Cardeza Foundation for Hematologic Research and Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Edelstein
authors.affiliation: Cardeza Foundation for Hematologic Research and Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Xianguo
authors.initials: X
authors.lastname: Kong
authors.affiliation: Cardeza Foundation for Hematologic Research and Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Seema
authors.initials: S
authors.lastname: Bhatlekar
authors.affiliation: Computational Medicine Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Isidore
authors.initials: I
authors.lastname: Rigoutsos
authors.affiliation: Cardeza Foundation for Hematologic Research and Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: paul.bray@jefferson.edu.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Bray
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Statistics, Rice University, Houston, TX 77251, USA. Electronic address: cashaw@bcm.edu.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
mesh_terms: D000483:Alleles; D001792:Blood Platelets / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; D022821:RNA Splice Sites; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human