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Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

Authors :
Mikhaylova AV
McHugh CP
Polfus LM
Raffield LM
Boorgula MP
Blackwell TW
Brody JA
Broome J
Chami N
Chen MH
Conomos MP
Cox C
Curran JE
Daya M
Ekunwe L
Glahn DC
Heard-Costa N
Highland HM
Hobbs BD
Ilboudo Y
Jain D
Lange LA
Miller-Fleming TW
Min N
Moon JY
Preuss MH
Rosen J
Ryan K
Smith AV
Sun Q
Surendran P
de Vries PS
Walter K
Wang Z
Wheeler M
Yanek LR
Zhong X
Abecasis GR
Almasy L
Barnes KC
Beaty TH
Becker LC
Blangero J
Boerwinkle E
Butterworth AS
Chavan S
Cho MH
Choquet H
Correa A
Cox N
DeMeo DL
Faraday N
Fornage M
Gerszten RE
Hou L
Johnson AD
Jorgenson E
Kaplan R
Kooperberg C
Kundu K
Laurie CA
Lettre G
Lewis JP
Li B
Li Y
Lloyd-Jones DM
Loos RJF
Manichaikul A
Meyers DA
Mitchell BD
Morrison AC
Ngo D
Nickerson DA
Nongmaithem S
North KE
O'Connell JR
Ortega VE
Pankratz N
Perry JA
Psaty BM
Rich SS
Soranzo N
Rotter JI
Silverman EK
Smith NL
Tang H
Tracy RP
Thornton TA
Vasan RS
Zein J
Mathias RA
Reiner AP
Auer PL
Source :
American journal of human genetics [Am J Hum Genet] 2021 Oct 07; Vol. 108 (10), pp. 1836-1851. Date of Electronic Publication: 2021 Sep 27.
Publication Year :
2021

Abstract

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2021 American Society of Human Genetics. All rights reserved.)

Details

Language :
English
ISSN :
1537-6605
Volume :
108
Issue :
10
Database :
MEDLINE
Journal :
American journal of human genetics
Publication Type :
Academic Journal
Accession number :
34582791
Full Text :
https://doi.org/10.1016/j.ajhg.2021.08.007