Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits.
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(-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.
1] School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA. [2] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Paul L
PL
Auer
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Alexander
000000028309094X
A
Teumer
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Ursula
U
Schick
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Andrew
A
O'Shaughnessy
Montreal Heart Institute, Montreal, Quebec, Canada.
Ken Sin
KS
Lo
Montreal Heart Institute, Montreal, Quebec, Canada.
Nathalie
N
Chami
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Chris
C
Carlson
1] Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. [3] Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada.
Simon
S
de Denus
1] Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. [3] Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada.
Marie-Pierre
MP
Dubé
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Jeff
J
Haessler
Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, Ohio, USA.
Rebecca D
RD
Jackson
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Charles
C
Kooperberg
Montreal Heart Institute, Montreal, Quebec, Canada.
Louis-Philippe Lemieux
LP
Perreault
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Matthias
M
Nauck
1] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
Ulrike
U
Peters
1] Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. [3] Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada.
John D
JD
Rioux
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Frank
F
Schmidt
Montreal Heart Institute, Montreal, Quebec, Canada.
Valérie
V
Turcot
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Uwe
U
Völker
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Henry
H
Völzke
Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
Andreas
A
Greinacher
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Li
L
Hsu
1] Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. [3] Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada.
Jean-Claude
JC
Tardif
1] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3].
George A
GA
Diaz
1] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA. [3].
Alexander P
AP
Reiner
1] Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. [3] Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada. [4].
Guillaume
G
Lettre
D000328:Adult; D000368:Aged; D002633:Chemotaxis; D000080984:Congenital Bone Marrow Failure Syndromes; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D055106:Genome-Wide Association Study; D005838:Genotype; D006400:Hematocrit; D006410:Hematopoiesis; D006454:Hemoglobins / Q000235:genetics*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics; D010375:Pedigree; D010976:Platelet Count; D023063:Receptors, Interleukin-8B / Q000235:genetics*
D006454:Hemoglobins; D023063:Receptors, Interleukin-8B; C507924:JAK2 protein, human; D053614:Janus Kinase 2