Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation

Ming Huei Chen, Lisa Yanek, Joshua D. Backman, John D. Eicher, Jennifer E. Huffman, Yoav Ben-Shlomo, Andrew D. Beswick, Laura M. Yerges-Armstrong, Alan R. Shuldiner, Jeffrey R. O’Connell, Rasika Mathias, Diane M Becker, Lewis Becker, Joshua P. Lewis, Andrew D. Johnson, Nauder Faraday

Research output: Contribution to journalArticle

Abstract

Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10–7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20–50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalPlatelets
DOIs
StateAccepted/In press - Nov 30 2017

Fingerprint

Exome
Platelet Aggregation
Meta-Analysis
Blood Platelets
Adenosine Diphosphate
Genome-Wide Association Study
Genotype
Genes
Phenotype
Platelet-Rich Plasma
Megakaryocytes
Isoleucine
Threonine
Heterozygote
Epigenomics
African Americans
Epinephrine
Proteins
Collagen
Nucleotides

Keywords

  • exome
  • genetic association
  • platelet aggregation
  • platelet reactivity
  • Platelets
  • SNP

ASJC Scopus subject areas

  • Hematology

Cite this

Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation. / Chen, Ming Huei; Yanek, Lisa; Backman, Joshua D.; Eicher, John D.; Huffman, Jennifer E.; Ben-Shlomo, Yoav; Beswick, Andrew D.; Yerges-Armstrong, Laura M.; Shuldiner, Alan R.; O’Connell, Jeffrey R.; Mathias, Rasika; Becker, Diane M; Becker, Lewis; Lewis, Joshua P.; Johnson, Andrew D.; Faraday, Nauder.

In: Platelets, 30.11.2017, p. 1-10.

Research output: Contribution to journalArticle

Chen, MH, Yanek, L, Backman, JD, Eicher, JD, Huffman, JE, Ben-Shlomo, Y, Beswick, AD, Yerges-Armstrong, LM, Shuldiner, AR, O’Connell, JR, Mathias, R, Becker, DM, Becker, L, Lewis, JP, Johnson, AD & Faraday, N 2017, 'Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation', Platelets, pp. 1-10. https://doi.org/10.1080/09537104.2017.1384538
Chen, Ming Huei ; Yanek, Lisa ; Backman, Joshua D. ; Eicher, John D. ; Huffman, Jennifer E. ; Ben-Shlomo, Yoav ; Beswick, Andrew D. ; Yerges-Armstrong, Laura M. ; Shuldiner, Alan R. ; O’Connell, Jeffrey R. ; Mathias, Rasika ; Becker, Diane M ; Becker, Lewis ; Lewis, Joshua P. ; Johnson, Andrew D. ; Faraday, Nauder. / Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation. In: Platelets. 2017 ; pp. 1-10.
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AU - Huffman, Jennifer E.

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