A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects

Khader Shameer, Joshua C. Denny, Keyue Ding, Hayan Jouni, David R. Crosslin, Mariza De Andrade, Christopher G. Chute, Peggy Peissig, Jennifer A. Pacheco, Rongling Li, Lisa Bastarache, Abel N. Kho, Marylyn D. Ritchie, Daniel R. Masys, Rex L. Chisholm, Eric B. Larson, Catherine A. McCarty, Dan M. Roden, Gail P. Jarvik, Iftikhar Jan Kullo

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (α: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (α: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.

Original languageEnglish (US)
Pages (from-to)95-109
Number of pages15
JournalHuman Genetics
Volume133
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Genome-Wide Association Study
Platelet Count
Mean Platelet Volume
Blood Platelets
Single Nucleotide Polymorphism
Electronic Health Records
Thrombopoiesis
Megakaryocytes
Hemostasis
Genetic Pleiotropy
Genetic Loci
Protein Subunits
Proteasome Endopeptidase Complex
Genes
Meta-Analysis
Signal Transduction
Membrane Proteins
Proteins
Transcription Factors
Phosphotransferases

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects. / Shameer, Khader; Denny, Joshua C.; Ding, Keyue; Jouni, Hayan; Crosslin, David R.; De Andrade, Mariza; Chute, Christopher G.; Peissig, Peggy; Pacheco, Jennifer A.; Li, Rongling; Bastarache, Lisa; Kho, Abel N.; Ritchie, Marylyn D.; Masys, Daniel R.; Chisholm, Rex L.; Larson, Eric B.; McCarty, Catherine A.; Roden, Dan M.; Jarvik, Gail P.; Kullo, Iftikhar Jan.

In: Human Genetics, Vol. 133, No. 1, 01.2014, p. 95-109.

Research output: Contribution to journalArticle

Shameer, K, Denny, JC, Ding, K, Jouni, H, Crosslin, DR, De Andrade, M, Chute, CG, Peissig, P, Pacheco, JA, Li, R, Bastarache, L, Kho, AN, Ritchie, MD, Masys, DR, Chisholm, RL, Larson, EB, McCarty, CA, Roden, DM, Jarvik, GP & Kullo, IJ 2014, 'A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects', Human Genetics, vol. 133, no. 1, pp. 95-109. https://doi.org/10.1007/s00439-013-1355-7
Shameer, Khader ; Denny, Joshua C. ; Ding, Keyue ; Jouni, Hayan ; Crosslin, David R. ; De Andrade, Mariza ; Chute, Christopher G. ; Peissig, Peggy ; Pacheco, Jennifer A. ; Li, Rongling ; Bastarache, Lisa ; Kho, Abel N. ; Ritchie, Marylyn D. ; Masys, Daniel R. ; Chisholm, Rex L. ; Larson, Eric B. ; McCarty, Catherine A. ; Roden, Dan M. ; Jarvik, Gail P. ; Kullo, Iftikhar Jan. / A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects. In: Human Genetics. 2014 ; Vol. 133, No. 1. pp. 95-109.
@article{4c5b58be841f40d484855973e3c3f77e,
title = "A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects",
abstract = "Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (α: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (α: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.",
author = "Khader Shameer and Denny, {Joshua C.} and Keyue Ding and Hayan Jouni and Crosslin, {David R.} and {De Andrade}, Mariza and Chute, {Christopher G.} and Peggy Peissig and Pacheco, {Jennifer A.} and Rongling Li and Lisa Bastarache and Kho, {Abel N.} and Ritchie, {Marylyn D.} and Masys, {Daniel R.} and Chisholm, {Rex L.} and Larson, {Eric B.} and McCarty, {Catherine A.} and Roden, {Dan M.} and Jarvik, {Gail P.} and Kullo, {Iftikhar Jan}",
year = "2014",
month = "1",
doi = "10.1007/s00439-013-1355-7",
language = "English (US)",
volume = "133",
pages = "95--109",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects

AU - Shameer, Khader

AU - Denny, Joshua C.

AU - Ding, Keyue

AU - Jouni, Hayan

AU - Crosslin, David R.

AU - De Andrade, Mariza

AU - Chute, Christopher G.

AU - Peissig, Peggy

AU - Pacheco, Jennifer A.

AU - Li, Rongling

AU - Bastarache, Lisa

AU - Kho, Abel N.

AU - Ritchie, Marylyn D.

AU - Masys, Daniel R.

AU - Chisholm, Rex L.

AU - Larson, Eric B.

AU - McCarty, Catherine A.

AU - Roden, Dan M.

AU - Jarvik, Gail P.

AU - Kullo, Iftikhar Jan

PY - 2014/1

Y1 - 2014/1

N2 - Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (α: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (α: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.

AB - Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (α: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (α: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.

UR - http://www.scopus.com/inward/record.url?scp=84891858260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891858260&partnerID=8YFLogxK

U2 - 10.1007/s00439-013-1355-7

DO - 10.1007/s00439-013-1355-7

M3 - Article

AN - SCOPUS:84891858260

VL - 133

SP - 95

EP - 109

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 1

ER -