title: Targeted deep resequencing identifies coding variants in the PEAR1 gene that play a role in platelet aggregation.
abstract: Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1) gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13) selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate). Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5%) were noted in African Americans compared to European Americans (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in African Americans (p = 4.020×10(-4)); no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331). Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965) supports the results noted in the sequenced discovery sample: p = 3.56×10(-4), 2.27×10(-7), 5.20×10(-5) for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans, and show that exonic variants play an additional role in platelet aggregation in European Americans.
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.forename: Bhoom
authors.initials: B
authors.lastname: Suktitipat
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Yanek
authors.forename: Nauder
authors.initials: N
authors.lastname: Faraday
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
authors.forename: Diane M
authors.initials: DM
authors.lastname: Becker
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Becker
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016366:Open Reading Frames / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C502809:PEAR1 protein, human; D011956:Receptors, Cell Surface