@article{1abcd87668e643cf9b7096cdf5e3d00a,
title = "Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation",
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.",
keywords = "Platelets, SNP, exome, genetic association, platelet aggregation, platelet reactivity",
author = "Chen, {Ming Huei} and Yanek, {Lisa R.} and Backman, {Joshua D.} and Eicher, {John D.} and Huffman, {Jennifer E.} and Yoav Ben-Shlomo and Beswick, {Andrew D.} and Yerges-Armstrong, {Laura M.} and Shuldiner, {Alan R.} and O{\textquoteright}Connell, {Jeffrey R.} and Mathias, {Rasika A.} and Becker, {Diane M.} and Becker, {Lewis C.} and Lewis, {Joshua P.} and Johnson, {Andrew D.} and Nauder Faraday",
note = "Funding Information: The Caerphilly Prospective study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the UK. The data archive is maintained by the School of Social and Community Medicine, University of Bristol. Funding Information: We thank all individuals for their participation in this study. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195). Genotyping, quality control, and calling of the Illumina HumanExome BeadChip in the Framingham Heart Study were supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O?Donnell, Principal Investigators). Support for the centralized genotype calling was provided by Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium through the National Institutes of Health (NIH) American Recovery and Reinvestment Act of 2009 (5RC2HL102419). M.H.C., J.D.E. and A.D.J. were supported by National Heart, Lung and Blood Institute Division of Intramural Research funds. GeneSTAR was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (U01 HL72518, HL087698, and HL112064) and by a grant from the National Institutes of Health/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. Genotyping services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under U.S. Federal Government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute. The Caerphilly Prospective study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the UK. The data archive is maintained by the School of Social and Community Medicine, University of Bristol. This investigation was also supported by National Institutes of Health grants U01 GM074518, U01 HL105198, K23 GM102678, and the University of Maryland Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488). This study makes use of data generated by the BLUEPRINT Consortium. A full list of the investigators who contributed to the generation of the data is available from www.blueprint-epigenome.eu. Funding for the project was provided by the European Union?s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 282510 BLUEPRINT. Funding Information: The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195). Genotyping, quality control, and calling of the Illumina HumanExome BeadChip in the Framingham Heart Study were supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O{\textquoteright}Donnell, Principal Investigators). Support for the centralized genotype calling was provided by Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium through the National Institutes of Health (NIH) American Recovery and Reinvestment Act of 2009 (5RC2HL102419). M.H.C., J.D.E. and A. D.J. were supported by National Heart, Lung and Blood Institute Division of Intramural Research funds. Funding Information: This study makes use of data generated by the BLUEPRINT Consortium. A full list of the investigators who contributed to the generation of the data is available from www.blueprint-epigenome.eu. Funding for the project was provided by the European Union{\textquoteright}s Seventh Framework Programme (FP7/ 2007-2013) under grant agreement no 282510 BLUEPRINT. Funding Information: This investigation was also supported by National Institutes of Health grants U01 GM074518, U01 HL105198, K23 GM102678, and the University of Maryland Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488). Funding Information: GeneSTAR was supported by the National Institutes of Health/ National Heart, Lung, and Blood Institute (U01 HL72518, HL087698, and HL112064) and by a grant from the National Institutes of Health/ National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. Genotyping services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under U.S. Federal Government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute. Publisher Copyright: {\textcopyright} 2017, {\textcopyright} 2017 Taylor & Francis.",
year = "2019",
month = feb,
day = "17",
doi = "10.1080/09537104.2017.1384538",
language = "English (US)",
volume = "30",
pages = "164--173",
journal = "Platelets",
issn = "0953-7104",
publisher = "Informa Healthcare",
number = "2",
}