Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits

Paul L. Auer; Alexander Teumer; Ursula Schick; Andrew O'Shaughnessy; Ken Sin Lo; Nathalie Chami; Chris Carlson; Simon De Denus; Marie Pierre Dubé; Jeff Haessler; Rebecca D. Jackson; Charles Kooperberg; Louis Philippe Lemieux Perreault; Matthias Nauck; Ulrike Peters; John D. Rioux; Frank Schmidt; Valérie Turcot; Uwe Völker; Henry Völzke; Andreas Greinacher; Li Hsu; Jean Claude Tardif; George A. Diaz; Alexander P. Reiner; Guillaume Lettre

doi:10.1038/ng.2962

Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits

Paul L. Auer, Alexander Teumer, Ursula Schick, Andrew O'Shaughnessy, Ken Sin Lo, Nathalie Chami, Chris Carlson, Simon De Denus, Marie Pierre Dubé, Jeff Haessler, Rebecca D. Jackson, Charles Kooperberg, Louis Philippe Lemieux Perreault, Matthias Nauck, Ulrike Peters, John D. Rioux, Frank Schmidt, Valérie Turcot, Uwe Völker, Henry VölzkeAndreas Greinacher, Li Hsu, Jean Claude Tardif, George A. Diaz, Alexander P. Reiner, Guillaume Lettre

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111 Scopus citations

Abstract

Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10 â ̂'13). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10^-22) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10^-7) and WBC count (P = 3.1 × 10 ^-5). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

Original language	English
Pages (from-to)	629-634
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	6
DOIs	https://doi.org/10.1038/ng.2962
State	Published - Jun 2014

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Auer, P. L., Teumer, A., Schick, U., O'Shaughnessy, A., Lo, K. S., Chami, N., Carlson, C., De Denus, S., Dubé, M. P., Haessler, J., Jackson, R. D., Kooperberg, C., Perreault, L. P. L., Nauck, M., Peters, U., Rioux, J. D., Schmidt, F., Turcot, V., Völker, U., ... Lettre, G. (2014). Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nature Genetics, 46(6), 629-634. https://doi.org/10.1038/ng.2962

@article{e485ae4ee59045fea93945ebca36ce40,

title = "Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits",

abstract = "Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10 {\^a}{\^ }'13). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10-22) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10-7) and WBC count (P = 3.1 × 10 -5). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.",

author = "Auer, \{Paul L.\} and Alexander Teumer and Ursula Schick and Andrew O'Shaughnessy and Lo, \{Ken Sin\} and Nathalie Chami and Chris Carlson and \{De Denus\}, Simon and Dub{\'e}, \{Marie Pierre\} and Jeff Haessler and Jackson, \{Rebecca D.\} and Charles Kooperberg and Perreault, \{Louis Philippe Lemieux\} and Matthias Nauck and Ulrike Peters and Rioux, \{John D.\} and Frank Schmidt and Val{\'e}rie Turcot and Uwe V{\"o}lker and Henry V{\"o}lzke and Andreas Greinacher and Li Hsu and Tardif, \{Jean Claude\} and Diaz, \{George A.\} and Reiner, \{Alexander P.\} and Guillaume Lettre",

note = "Funding Information: We thank all participants and staff of the MHI Biobank and acknowledge the technical support of the Beaulieu-Saucier MHI Pharmacogenomic Center. This work was supported by the Centre of Excellence in Personalized Medicine (CEPMed), Fonds de Recherche du Qu{\'e}bec–Sant{\'e} (FRQS), the Canada Research Chair program and the MHI Foundation. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C). Exome chip data and analysis were supported through the Exome Sequencing Project (NHLBI RC2 HL-102924, RC2 HL-102925 and RC2 HL-102926), the Genetics and Epidemiology of Colorectal Cancer Consortium (NCI CA137088), the Genomics and Randomized Trials Network (NHGRI U01-HG005152) and a National Cancer Institute training grant (R25CA094880). The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. SHIP is part of the Community Medicine Research network of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg–West Pomerania, and the network Greifswald Approach to Individualized Medicine (GANI\_MED) funded by the Federal Ministry of Education and Research (grant 03IS2061A). Generation of ExomeChip data has been supported by the Federal Ministry of Education and Research (grant 03Z1CN22) and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of Siemens AG and the Cach{\'e} Campus program of InterSystems. G.A.D. acknowledges support from US National Institutes of Health award P01AI061093.",

year = "2014",

month = jun,

doi = "10.1038/ng.2962",

language = "English",

volume = "46",

pages = "629--634",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Auer, PL, Teumer, A, Schick, U, O'Shaughnessy, A, Lo, KS, Chami, N, Carlson, C, De Denus, S, Dubé, MP, Haessler, J, Jackson, RD, Kooperberg, C, Perreault, LPL, Nauck, M, Peters, U, Rioux, JD, Schmidt, F, Turcot, V, Völker, U, Völzke, H, Greinacher, A, Hsu, L, Tardif, JC, Diaz, GA, Reiner, AP & Lettre, G 2014, 'Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits', Nature Genetics, vol. 46, no. 6, pp. 629-634. https://doi.org/10.1038/ng.2962

TY - JOUR

T1 - Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits

AU - Auer, Paul L.

AU - Teumer, Alexander

AU - Schick, Ursula

AU - O'Shaughnessy, Andrew

AU - Lo, Ken Sin

AU - Chami, Nathalie

AU - Carlson, Chris

AU - De Denus, Simon

AU - Dubé, Marie Pierre

AU - Haessler, Jeff

AU - Jackson, Rebecca D.

AU - Kooperberg, Charles

AU - Perreault, Louis Philippe Lemieux

AU - Nauck, Matthias

AU - Peters, Ulrike

AU - Rioux, John D.

AU - Schmidt, Frank

AU - Turcot, Valérie

AU - Völker, Uwe

AU - Völzke, Henry

AU - Greinacher, Andreas

AU - Hsu, Li

AU - Tardif, Jean Claude

AU - Diaz, George A.

AU - Reiner, Alexander P.

AU - Lettre, Guillaume

N1 - Funding Information: We thank all participants and staff of the MHI Biobank and acknowledge the technical support of the Beaulieu-Saucier MHI Pharmacogenomic Center. This work was supported by the Centre of Excellence in Personalized Medicine (CEPMed), Fonds de Recherche du Québec–Santé (FRQS), the Canada Research Chair program and the MHI Foundation. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C). Exome chip data and analysis were supported through the Exome Sequencing Project (NHLBI RC2 HL-102924, RC2 HL-102925 and RC2 HL-102926), the Genetics and Epidemiology of Colorectal Cancer Consortium (NCI CA137088), the Genomics and Randomized Trials Network (NHGRI U01-HG005152) and a National Cancer Institute training grant (R25CA094880). The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. SHIP is part of the Community Medicine Research network of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg–West Pomerania, and the network Greifswald Approach to Individualized Medicine (GANI_MED) funded by the Federal Ministry of Education and Research (grant 03IS2061A). Generation of ExomeChip data has been supported by the Federal Ministry of Education and Research (grant 03Z1CN22) and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of Siemens AG and the Caché Campus program of InterSystems. G.A.D. acknowledges support from US National Institutes of Health award P01AI061093.

PY - 2014/6

Y1 - 2014/6

N2 - Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10 â ̂'13). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10-22) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10-7) and WBC count (P = 3.1 × 10 -5). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

AB - Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10 â ̂'13). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10-22) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10-7) and WBC count (P = 3.1 × 10 -5). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

UR - https://www.scopus.com/pages/publications/84901684867

U2 - 10.1038/ng.2962

DO - 10.1038/ng.2962

M3 - Article

C2 - 24777453

AN - SCOPUS:84901684867

SN - 1061-4036

VL - 46

SP - 629

EP - 634

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits

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