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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association
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Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association

机译：连锁分析确定了全基因组关联未检测到的血浆von Willebrand因子的基因座

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Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109;Howard Hughes Medical Institute, Ann Arbor, Ml, 48109;Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;Department of Pediatrics, Duke University, Durham, NC 27710;Department of Pediatrics, Northwestern University, Chicago, IL 60611;Department of Biostatistics, University of Washington, Seattle, WA 98105;Department of Biostatistics, University of Washington, Seattle, WA 98105;Broad Institute of MIT and Harvard, Cambridge, MA 02142;Broad Institute of MIT and Harvard, Cambridge, MA 02142;Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224;Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224;Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109,Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109,Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109,Howard Hughes Medical Institute, Ann Arbor, Ml, 48109,Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;%The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12-2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the "missing heritability" for other complex genetic traits.
机译：密歇根大学安阿伯密歇根分校儿科和传染病系;密歇根州48109;密歇根大学安阿伯密歇根大学人类遗传学系;密歇根州安阿伯霍华德休斯医学研究所48109;哈达萨-希伯来大学医学中心，以色列耶路撒冷91120；密歇根大学儿科与传染病系，密歇根州安阿伯市48109；杜克大学儿科，达勒姆，北卡罗来纳州27710；西北大学儿科，芝加哥，伊利诺斯州60611；生物统计学系，华盛顿大学，西雅图，WA 98105；生物统计学系，华盛顿大学，西雅图，WA 98105；麻省理工学院与哈佛大学，剑桥，MA 02142；麻省理工学院与哈佛大学，剑桥，MA 02142；遗传病研究美国国立卫生研究院国家人类基因组研究所，医学博士，马里兰州21224；美国国家人类基因组研究所遗传病研究科，美国f卫生部，马里兰州马里兰州21224;密歇根大学儿科与传染病系，密歇根州安阿伯市48109;密歇根大学儿科与传染病系，密歇根州安阿伯市，密西根州48109;国家人类基因组遗传病研究部门美国马里兰州巴尔的摩国家卫生研究所，医学博士21224;美国国家卫生研究所，国家人类基因组研究所遗传病研究室，马里兰州21224;密歇根大学儿科和传染病系，密西根州安娜堡48109 ；密歇根大学儿科与传染病系，密歇根州安阿伯市48109；密歇根大学儿科与传染病系，密歇根州安阿伯市48109；密歇根大学人类遗传学系，密歇根州安阿伯市48109，密歇根大学儿科与传染病系，密歇根州安娜堡48109；大学o儿科与传染病系f密歇根州安娜堡市密歇根州48109，密歇根大学人类遗传学系，密歇根州48109霍华德·休斯医学研究所，密苏里州安阿伯市48109，密歇根大学儿科与传染病系MI 48109;％血浆糖蛋白von Willebrand因子（VWF）在正常人群中表现出五倍的抗原水平变化，这是由遗传和环境因素决定的。低水平的VWF与出血有关，水平升高会增加血栓形成，心肌梗塞和中风的风险。为了确定VWF抗原水平的其他遗传决定因素，并最大程度地减少年龄和疾病相关环境因素的影响，我们在两个年轻且健康的队列（n = 1,152和n = 2,310）中进行了全基因组关联分析，并在ABO处鉴定了信号（P <7.9E-139）和VWF（P <5.5E-16），与以前的报告一致。此外，基于队列中同胞结构的连锁分析确定了染色体2q12-2p13（LOD得分5.3）和染色体9q34的ABO位点（LOD得分2.9）的重要信号，这些信号解释了VWF变异的19.2％和24.5％。级别。鉴于其强大的作用，2号染色体上的连接区域可能具有潜在的重要决定因素，即出血和血栓形成的风险。在此或先前的关联研究中，没有2号染色体关联信号提示了一个致病基因，其中包含许多遗传变体，这些变体个别罕见，但总体上很常见。这些结果增加了类似的基因座可以解释其他复杂遗传特征的“遗漏遗传力”的很大一部分的可能性。

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  • 作者

    Karl C. Desch; Ayse B. Ozel; David Siemieniak; Yossi Kalish; Jordan A. Shavit; Courtney D. Thornburg; Anjali A. Sharathkumar; Caitlin P. McHugh; Cathy C. Laurie; Andrew Crenshaw; Daniel B. Mirel; Yoonhee Kim; Cheryl D. Cropp; Anne M. Molloy; Peadar N. Kirke; Joan E. Bailey-Wilson; Alexander F. Wilson; James L. Mills; John M. Scott; Lawrence C. Brody; Jun Z. Li; David Ginsburg;

  • 作者单位

    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

    Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109;

    Howard Hughes Medical Institute, Ann Arbor, Ml, 48109;

    Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;

    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

    Department of Pediatrics, Duke University, Durham, NC 27710;

    Department of Pediatrics, Northwestern University, Chicago, IL 60611;

    Department of Biostatistics, University of Washington, Seattle, WA 98105;

    Department of Biostatistics, University of Washington, Seattle, WA 98105;

    Broad Institute of MIT and Harvard, Cambridge, MA 02142;

    Broad Institute of MIT and Harvard, Cambridge, MA 02142;

    Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224;

    Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224;

    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

    Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224;

    Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224;

    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

    Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109,Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

    Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109,Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109,Howard Hughes Medical Institute, Ann Arbor, Ml, 48109,Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    genome-wide association study; linkage study; venous thromboembolic disease; von willebrand disease; quantitative trait loci;

    机译：全基因组关联研究;关联研究;静脉血栓栓塞性疾病von willebrand病;数量性状基因座;

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