TY - JOUR
T1 - Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits
T2 - The NHLBI TOPMed program
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - Mikhaylova, Anna V.
AU - McHugh, Caitlin P.
AU - Polfus, Linda M.
AU - Raffield, Laura M.
AU - Boorgula, Meher Preethi
AU - Blackwell, Thomas W.
AU - Brody, Jennifer A.
AU - Broome, Jai
AU - Chami, Nathalie
AU - Chen, Ming Huei
AU - Conomos, Matthew P.
AU - Cox, Corey
AU - Curran, Joanne E.
AU - Daya, Michelle
AU - Ekunwe, Lynette
AU - Glahn, David C.
AU - Heard-Costa, Nancy
AU - Highland, Heather M.
AU - Hobbs, Brian D.
AU - Ilboudo, Yann
AU - Jain, Deepti
AU - Lange, Leslie A.
AU - Miller-Fleming, Tyne W.
AU - Min, Nancy
AU - Moon, Jee Young
AU - Preuss, Michael H.
AU - Rosen, Jonathon
AU - Ryan, Kathleen
AU - Smith, Albert V.
AU - Sun, Quan
AU - Surendran, Praveen
AU - de Vries, Paul S.
AU - Walter, Klaudia
AU - Wang, Zhe
AU - Wheeler, Marsha
AU - Yanek, Lisa R.
AU - Zhong, Xue
AU - Abecasis, Goncalo R.
AU - Almasy, Laura
AU - Barnes, Kathleen C.
AU - Beaty, Terri H.
AU - Becker, Lewis C.
AU - Blangero, John
AU - Boerwinkle, Eric
AU - Butterworth, Adam S.
AU - Chavan, Sameer
AU - Cho, Michael H.
AU - Choquet, Hélène
AU - Correa, Adolfo
AU - Kaplan, Robert
N1 - Funding Information:
Molecular data for the TOPMed program was supported by the National Heart, Lung and Blood Institute (NHLBI). Study-specific omics support information can be found in the supplement. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center ( 3R01HL-117626-02S1 ; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination, were provided by the TOPMed Data Coordinating Center ( R01HL-120393 ; U01HL-120393; contract HHSN268201800001I). The project described was also supported by the National Center for Advancing Translational Sciences , National Institutes of Health , through grant KL2TR002490 (L.M.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. L.M.R. was additionally funded by the NIH grants R01HL129132 and T32 HL129982 . P.L.A. was funded by the NIH grant R01HL130733 . P.S.d.V. was supported by American Heart Association grant number 18CDA34110116 . We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed.
Funding Information:
Molecular data for the TOPMed program was supported by the National Heart, Lung and Blood Institute (NHLBI). Study-specific omics support information can be found in the supplement. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination, were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The project described was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant KL2TR002490 (L.M.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. L.M.R. was additionally funded by the NIH grants R01HL129132 and T32 HL129982. P.L.A. was funded by the NIH grant R01HL130733. P.S.d.V. was supported by American Heart Association grant number 18CDA34110116. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The authors declare no competing interests.
Publisher Copyright:
© 2021 American Society of Human Genetics
PY - 2021/10/7
Y1 - 2021/10/7
N2 - 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.
AB - 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.
KW - blood-cell counts
KW - whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85116865932&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116865932&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2021.08.007
DO - 10.1016/j.ajhg.2021.08.007
M3 - Article
C2 - 34582791
AN - SCOPUS:85116865932
SN - 0002-9297
VL - 108
SP - 1836
EP - 1851
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 10
ER -