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A Genome-wide Association Study Identifies Three Loci Associated with Mean Platelet Volume

By Christa Meisinger, Holger Prokisch, Christian Gieger, Nicole Soranzo, Divya Mehta, Dieter Rosskopf, Peter Lichtner, Norman Klopp, Jonathan Stephens, Nicholas A. Watkins, Panos Deloukas, Andreas Greinacher, Wolfgang Koenig, Matthias Nauck, Christian Rimmbach, Henry Völzke, Annette Peters, Thomas Illig, Willem H. Ouwehand, Thomas Meitinger, H.-Erich Wichmann and Angela Döring

Abstract

Mean platelet volume (MPV) is increased in myocardial and cerebral infarction and is an independent and strong predictor for postevent morbidity and mortality. We conducted a genome-wide association study (GWAS), the KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K study, and found MPV to be strongly associated with three common single-nucleotide polymorphisms (SNPs): rs7961894 located within intron 3 of WDR66 on chromosome 12q24.31, rs12485738 upstream of the ARHGEF3 on chromosome 3p13-p21, and rs2138852 located upstream of TAOK1 on chromosome 17q11.2. We replicated all three SNPs in another GWAS from the UK and in two population-based samples from Germany. In a combined analysis including 10,048 subjects, the SNPs had p values of 7.24 × 10−48 for rs7961894, 3.81 × 10−27 for rs12485738, and 7.19 × 10−28 for rs2138852. These three quantitative trait loci together accounted for 4%–5% of the variance in MPV. In-depth sequence analysis of WDR66 in 382 samples from the extremes revealed 20 new variants and a haplotype with three coding SNPs and one SNP at the transcription start site associated with MPV (p = 6.8 × 10−5). In addition, expression analysis indicated a direct correlation of WDR66 transcripts and MPV. These findings may not only enhance our understanding of platelet activation and function, but may also provide a focus for several novel research avenues

Topics: Report
Publisher: Elsevier
OAI identifier: oai:pubmedcentral.nih.gov:2668036
Provided by: PubMed Central
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