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 Deriggi 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

33 Citations (Scopus)

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

Fingerprint

Monocytes
Genes
Joints
Lysophosphatidic Acid Receptors
Integrin alpha Chains
Chromosomes, Human, Pair 16
Chromosomes, Human, Pair 9
Chromosomes, Human, Pair 3
Chromosomes, Human, Pair 2
Electronic Health Records
Atherosclerotic Plaques
Genomics
Leukocyte Count
Vascular Diseases
Prostaglandins
Coronary Disease
Oxidoreductases
Leukocytes
Chronic Disease
Genome

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Crosslin, D. R., McDavid, A., Weston, N., Zheng, X., Hart, E., de Andrade, M., ... 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
Crosslin, David R. ; McDavid, Andrew ; Weston, Noah ; Zheng, Xiuwen ; Hart, Eugene ; de Andrade, Mariza ; Kullo, Iftikhar J. ; McCarty, Catherine A. ; Doheny, Kimberly F. ; Pugh, Elizabeth ; Kho, Abel ; Hayes, M. Geoffrey ; Ritchie, Marylyn Deriggi ; Saip, Alexander ; Crawford, Dana C. ; Crane, Paul K. ; Newton, Katherine ; Carrell, David S. ; Gallego, Carlos J. ; Nalls, Michael A. ; Li, Rongling ; Mirel, Daniel B. ; Crenshaw, Andrew ; Couper, David J. ; Tanaka, Toshiko ; van Rooij, Frank J.A. ; Chen, Ming Huei ; Smith, Albert V. ; Zakai, Neil A. ; Yango, Qiong ; Garcia, Melissa ; Liu, Yongmei ; Lumley, Thomas ; Folsom, Aaron R. ; Reiner, Alex P. ; Felix, Janine F. ; Dehghan, Abbas ; Wilson, James G. ; Bis, Joshua C. ; Fox, Caroline S. ; Glazer, Nicole L. ; Cupples, L. Adrienne ; Coresh, Josef ; Eiriksdottir, Gudny ; Gudnason, Vilmundur ; Bandinelli, Stefania ; Frayling, Timothy M. ; Chakravarti, Aravinda ; van Duijn, Cornelia M. ; Melzer, David ; Levy, Daniel ; Boerwinkle, Eric ; Singleton, Andrew B. ; Hernandez, Dena G. ; Longo, Dan L. ; Witteman, Jacqueline C.M. ; Psaty, Bruce M. ; Ferrucci, Luigi ; Harris, Tamara B. ; O'Donnell, Christopher J. ; Ganesh, Santhi K. ; Larson, Eric B. ; Carlson, Chris S. ; Jarvik, Gail P. / Genetic variation associated with circulating monocyte count in the eMERGE Network. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 10. pp. 2119-2127.
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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.",
author = "Crosslin, {David R.} and Andrew McDavid and Noah Weston and Xiuwen Zheng and Eugene Hart and {de Andrade}, Mariza and Kullo, {Iftikhar J.} and McCarty, {Catherine A.} and Doheny, {Kimberly F.} and Elizabeth Pugh and Abel Kho and Hayes, {M. Geoffrey} and Ritchie, {Marylyn Deriggi} and Alexander Saip and Crawford, {Dana C.} and Crane, {Paul K.} and Katherine Newton and Carrell, {David S.} and Gallego, {Carlos J.} and Nalls, {Michael A.} and Rongling Li and Mirel, {Daniel B.} and Andrew Crenshaw and Couper, {David J.} and Toshiko Tanaka and {van Rooij}, {Frank J.A.} and Chen, {Ming Huei} and Smith, {Albert V.} and Zakai, {Neil A.} and Qiong Yango and Melissa Garcia and Yongmei Liu and Thomas Lumley and Folsom, {Aaron R.} and Reiner, {Alex P.} and Felix, {Janine F.} and Abbas Dehghan and Wilson, {James G.} and Bis, {Joshua C.} and Fox, {Caroline S.} and Glazer, {Nicole L.} and Cupples, {L. Adrienne} and Josef Coresh and Gudny Eiriksdottir and Vilmundur Gudnason and Stefania Bandinelli and Frayling, {Timothy M.} and Aravinda Chakravarti and {van Duijn}, {Cornelia M.} and David Melzer and Daniel Levy and Eric Boerwinkle and Singleton, {Andrew B.} and Hernandez, {Dena G.} and Longo, {Dan L.} and Witteman, {Jacqueline C.M.} and Psaty, {Bruce M.} and Luigi Ferrucci and Harris, {Tamara B.} and O'Donnell, {Christopher J.} and Ganesh, {Santhi K.} and Larson, {Eric B.} and Carlson, {Chris S.} and Jarvik, {Gail P.}",
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Crosslin, DR, McDavid, A, Weston, N, Zheng, X, Hart, E, de Andrade, M, Kullo, IJ, McCarty, CA, Doheny, KF, Pugh, E, Kho, A, Hayes, MG, Ritchie, MD, Saip, A, Crawford, DC, Crane, PK, Newton, K, Carrell, DS, Gallego, CJ, Nalls, MA, Li, R, Mirel, DB, Crenshaw, A, Couper, DJ, Tanaka, T, van Rooij, FJA, Chen, MH, Smith, AV, Zakai, NA, Yango, Q, Garcia, M, Liu, Y, Lumley, T, Folsom, AR, Reiner, AP, Felix, JF, Dehghan, A, Wilson, JG, Bis, JC, Fox, CS, Glazer, NL, Cupples, LA, Coresh, J, Eiriksdottir, G, Gudnason, V, Bandinelli, S, Frayling, TM, Chakravarti, A, van Duijn, CM, Melzer, D, Levy, D, Boerwinkle, E, Singleton, AB, Hernandez, DG, Longo, DL, Witteman, JCM, Psaty, BM, Ferrucci, L, Harris, TB, O'Donnell, CJ, Ganesh, SK, Larson, EB, Carlson, CS & Jarvik, GP 2013, 'Genetic variation associated with circulating monocyte count in the eMERGE Network', Human Molecular Genetics, vol. 22, no. 10, pp. 2119-2127. https://doi.org/10.1093/hmg/ddt010

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

In: Human Molecular Genetics, Vol. 22, No. 10, 01.05.2013, p. 2119-2127.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic variation associated with circulating monocyte count in the eMERGE Network

AU - Crosslin, David R.

AU - McDavid, Andrew

AU - Weston, Noah

AU - Zheng, Xiuwen

AU - Hart, Eugene

AU - de Andrade, Mariza

AU - Kullo, Iftikhar J.

AU - McCarty, Catherine A.

AU - Doheny, Kimberly F.

AU - Pugh, Elizabeth

AU - Kho, Abel

AU - Hayes, M. Geoffrey

AU - Ritchie, Marylyn Deriggi

AU - Saip, Alexander

AU - Crawford, Dana C.

AU - Crane, Paul K.

AU - Newton, Katherine

AU - Carrell, David S.

AU - Gallego, Carlos J.

AU - Nalls, Michael A.

AU - Li, Rongling

AU - Mirel, Daniel B.

AU - Crenshaw, Andrew

AU - Couper, David J.

AU - Tanaka, Toshiko

AU - van Rooij, Frank J.A.

AU - Chen, Ming Huei

AU - Smith, Albert V.

AU - Zakai, Neil A.

AU - Yango, Qiong

AU - Garcia, Melissa

AU - Liu, Yongmei

AU - Lumley, Thomas

AU - Folsom, Aaron R.

AU - Reiner, Alex P.

AU - Felix, Janine F.

AU - Dehghan, Abbas

AU - Wilson, James G.

AU - Bis, Joshua C.

AU - Fox, Caroline S.

AU - Glazer, Nicole L.

AU - Cupples, L. Adrienne

AU - Coresh, Josef

AU - Eiriksdottir, Gudny

AU - Gudnason, Vilmundur

AU - Bandinelli, Stefania

AU - Frayling, Timothy M.

AU - Chakravarti, Aravinda

AU - van Duijn, Cornelia M.

AU - Melzer, David

AU - Levy, Daniel

AU - Boerwinkle, Eric

AU - Singleton, Andrew B.

AU - Hernandez, Dena G.

AU - Longo, Dan L.

AU - Witteman, Jacqueline C.M.

AU - Psaty, Bruce M.

AU - Ferrucci, Luigi

AU - Harris, Tamara B.

AU - O'Donnell, Christopher J.

AU - Ganesh, Santhi K.

AU - Larson, Eric B.

AU - Carlson, Chris S.

AU - Jarvik, Gail P.

PY - 2013/5/1

Y1 - 2013/5/1

N2 - 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.

AB - 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.

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Crosslin DR, McDavid A, Weston N, Zheng X, Hart E, de Andrade M et al. Genetic variation associated with circulating monocyte count in the eMERGE Network. Human Molecular Genetics. 2013 May 1;22(10):2119-2127. https://doi.org/10.1093/hmg/ddt010