Genetic variation associated with circulating monocyte count in the eMERGE Network

David R. Crosslin, Andrew McDavid, Noah Weston, Xiuwen Zheng, Eugene Hart, Mariza de Andrade, Iftikhar J. Kullo, Catherine A. McCarty, Kimberly F. Doheny, Elizabeth Pugh, Abel Kho, M. Geoffrey Hayes, Marylyn D. Ritchie, Alexander Saip, Dana C. Crawford, Paul K. Crane, Katherine Newton, David S. Carrell, Carlos J. Gallego, Michael A. NallsRongling Li, Daniel B. Mirel, Andrew Crenshaw, David J. Couper, Toshiko Tanaka, Frank J.A. van Rooij, Ming Huei Chen, Albert V. Smith, Neil A. Zakai, Qiong Yango, Melissa Garcia, Yongmei Liu, Thomas Lumley, Aaron R. Folsom, Alex P. Reiner, Janine F. Felix, Abbas Dehghan, James G. Wilson, Joshua C. Bis, Caroline S. Fox, Nicole L. Glazer, L. Adrienne Cupples, Josef Coresh, Gudny Eiriksdottir, Vilmundur Gudnason, Stefania Bandinelli, Timothy M. Frayling, Aravinda Chakravarti, Cornelia M. van Duijn, David Melzer, Daniel Levy, Eric Boerwinkle, Andrew B. Singleton, Dena G. Hernandez, Dan L. Longo, Jacqueline C.M. Witteman, Bruce M. Psaty, Luigi Ferrucci, Tamara B. Harris, Christopher J. O'Donnell, Santhi K. Ganesh, Eric B. Larson, Chris S. Carlson, Gail P. Jarvik

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genomewide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value =2.7x10(-16), β=-0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value =1.88x10(-7), β=0.30) and a region of replication found in ribophorin I (RPN1) (P-value=2.63x10(-16), β=-0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value =2.29x10(-7), β=0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value =5.68x10(-17), β=-0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.

Original languageEnglish (US)
Pages (from-to)2119-2127
Number of pages9
JournalHuman molecular genetics
Volume22
Issue number10
DOIs
StatePublished - May 1 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Crosslin, D. R., McDavid, A., Weston, N., Zheng, X., Hart, E., de Andrade, M., Kullo, I. J., McCarty, C. A., Doheny, K. F., Pugh, E., Kho, A., Hayes, M. G., Ritchie, M. D., Saip, A., Crawford, D. C., Crane, P. K., Newton, K., Carrell, D. S., Gallego, C. J., ... Jarvik, G. P. (2013). Genetic variation associated with circulating monocyte count in the eMERGE Network. Human molecular genetics, 22(10), 2119-2127. https://doi.org/10.1093/hmg/ddt010