TY - JOUR
T1 - A Genome-wide Association Study Identifies Three Loci Associated with Mean Platelet Volume
AU - Meisinger, Christa
AU - Prokisch, Holger
AU - Gieger, Christian
AU - Soranzo, Nicole
AU - Mehta, Divya
AU - Rosskopf, Dieter
AU - Lichtner, Peter
AU - Klopp, Norman
AU - Stephens, Jonathan
AU - Watkins, Nicholas A.
AU - Deloukas, Panos
AU - Greinacher, Andreas
AU - Koenig, Wolfgang
AU - Nauck, Matthias
AU - Rimmbach, Christian
AU - Völzke, Henry
AU - Peters, Annette
AU - Illig, Thomas
AU - Ouwehand, Willem H.
AU - Meitinger, Thomas
AU - Wichmann, H. Erich
AU - Döring, Angela
N1 - Funding Information:
The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was funded by the German National Genome Research Network (NGFN) and the European Union-sponsored project Cardiogenetics (LSH-2005-037593). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. SHIP is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The SHIP genotyping was supported by the future fund of the state government of Mecklenburg-Vorpommern (UG 07 034). The establishment and genotyping of the UKBS-CC1 collection was funded by the Wellcome Trust and by a National Institutes of Health Research Grant to NHSBT. We thank the staff of the DNA Collections and Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation. We gratefully acknowledge the contribution of G. Eckstein, T. Strom and K. Heim, A. Löschner, R. Hellinger, and all other members of the Helmholtz Zentrum München genotyping staff in generating and analyzing the SNP and RNA data set and G. Fischer and B. Kühnel for data management and statistical analyses. We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg, UKBS-CC1, and SHIP studies. Finally, we express our appreciation to all study participants. No conflict of interest relevant to this article was reported.
PY - 2009/1/9
Y1 - 2009/1/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=58049220179&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2008.11.015
DO - 10.1016/j.ajhg.2008.11.015
M3 - Article
C2 - 19110211
AN - SCOPUS:58049220179
SN - 0002-9297
VL - 84
SP - 66
EP - 71
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -