Clinical associations with a polygenic predisposition to benign lower white blood cell counts

Jonathan D. Mosley; John P. Shelley; Alyson L. Dickson; Jacy Zanussi; Laura L. Daniel; Neil S. Zheng; Lisa Bastarache; Wei Qi Wei; Mingjian Shi; Gail P. Jarvik; Elisabeth A. Rosenthal; Atlas Khan; Alborz Sherafati; Iftikhar J. Kullo; Theresa L. Walunas; Joseph Glessner; Hakon Hakonarson; Nancy J. Cox; Dan M. Roden; Stephan G. Frangakis; Brett Vanderwerff; C. Michael Stein; Sara L. Van Driest; Scott C. Borinstein; Xiao Ou Shu; Matthew Zawistowski; Cecilia P. Chung; Vivian K. Kawai

doi:10.1038/s41467-024-47804-5

Clinical associations with a polygenic predisposition to benign lower white blood cell counts

Jonathan D. Mosley^*, John P. Shelley, Alyson L. Dickson, Jacy Zanussi, Laura L. Daniel, Neil S. Zheng, Lisa Bastarache, Wei Qi Wei, Mingjian Shi, Gail P. Jarvik, Elisabeth A. Rosenthal, Atlas Khan, Alborz Sherafati, Iftikhar J. Kullo, Theresa L. Walunas, Joseph Glessner, Hakon Hakonarson, Nancy J. Cox, Dan M. Roden, Stephan G. FrangakisBrett Vanderwerff, C. Michael Stein, Sara L. Van Driest, Scott C. Borinstein, Xiao Ou Shu, Matthew Zawistowski, Cecilia P. Chung, Vivian K. Kawai

^*Corresponding author for this work

Medicine, General Medicine Division

Research output: Contribution to journal › Article › peer-review

Abstract

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGS_WBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGS_WBC [95%CI, 0.30−0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69−0.88], p = 4.0 × 10⁻⁵) or immunosuppressant (n = 354, HR = 0.61 [0.38–0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44−0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Original language	English (US)
Article number	3384
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-47804-5
State	Published - Dec 2024

Funding

The authors acknowledge the MGI participants, Precision Health at the UM, the UM Medical School Central Biorepository, and the UM Advanced Genomics Core for providing data and specimen storage, management, processing, and distribution services and the Center for Statistical Genetics in the Department of Biostatistics at the School of Public Health for genotype data curation, imputation, and management in support of the research reported in this publication. This work was supported by the NIH R01GM130791 (J.D.M.), R01GM126535 (C.P.C.), R35GM131770 (C.M.S.), U01HG011181 (D.M.R.) and the Ingram Cancer Research Professorship fund (X.S.). Vanderbilt University Medical Center\u2019s BioVU is supported by institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141; and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/. REDCap is supported by UL1TR000445 from NCATS/NIH. eMERGE is funded by U01HG006828 (Cincinnati Children\u2019s Hospital Medical Center/Boston Children\u2019s Hospital); U01HG006830 (Children\u2019s Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center), U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Mosley, J. D., Shelley, J. P., Dickson, A. L., Zanussi, J., Daniel, L. L., Zheng, N. S., Bastarache, L., Wei, W. Q., Shi, M., Jarvik, G. P., Rosenthal, E. A., Khan, A., Sherafati, A., Kullo, I. J., Walunas, T. L., Glessner, J., Hakonarson, H., Cox, N. J., Roden, D. M., ... Kawai, V. K. (2024). Clinical associations with a polygenic predisposition to benign lower white blood cell counts. Nature communications, 15(1), Article 3384. https://doi.org/10.1038/s41467-024-47804-5

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title = "Clinical associations with a polygenic predisposition to benign lower white blood cell counts",

abstract = "Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30−0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69−0.88], p = 4.0 × 10−5) or immunosuppressant (n = 354, HR = 0.61 [0.38–0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44−0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.",

author = "Mosley, {Jonathan D.} and Shelley, {John P.} and Dickson, {Alyson L.} and Jacy Zanussi and Daniel, {Laura L.} and Zheng, {Neil S.} and Lisa Bastarache and Wei, {Wei Qi} and Mingjian Shi and Jarvik, {Gail P.} and Rosenthal, {Elisabeth A.} and Atlas Khan and Alborz Sherafati and Kullo, {Iftikhar J.} and Walunas, {Theresa L.} and Joseph Glessner and Hakon Hakonarson and Cox, {Nancy J.} and Roden, {Dan M.} and Frangakis, {Stephan G.} and Brett Vanderwerff and Stein, {C. Michael} and {Van Driest}, {Sara L.} and Borinstein, {Scott C.} and Shu, {Xiao Ou} and Matthew Zawistowski and Chung, {Cecilia P.} and Kawai, {Vivian K.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-47804-5",

language = "English (US)",

volume = "15",

journal = "Nature communications",

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Mosley, JD, Shelley, JP, Dickson, AL, Zanussi, J, Daniel, LL, Zheng, NS, Bastarache, L, Wei, WQ, Shi, M, Jarvik, GP, Rosenthal, EA, Khan, A, Sherafati, A, Kullo, IJ, Walunas, TL, Glessner, J, Hakonarson, H, Cox, NJ, Roden, DM, Frangakis, SG, Vanderwerff, B, Stein, CM, Van Driest, SL, Borinstein, SC, Shu, XO, Zawistowski, M, Chung, CP & Kawai, VK 2024, 'Clinical associations with a polygenic predisposition to benign lower white blood cell counts', Nature communications, vol. 15, no. 1, 3384. https://doi.org/10.1038/s41467-024-47804-5

TY - JOUR

T1 - Clinical associations with a polygenic predisposition to benign lower white blood cell counts

AU - Mosley, Jonathan D.

AU - Shelley, John P.

AU - Dickson, Alyson L.

AU - Zanussi, Jacy

AU - Daniel, Laura L.

AU - Zheng, Neil S.

AU - Bastarache, Lisa

AU - Wei, Wei Qi

AU - Shi, Mingjian

AU - Jarvik, Gail P.

AU - Rosenthal, Elisabeth A.

AU - Khan, Atlas

AU - Sherafati, Alborz

AU - Kullo, Iftikhar J.

AU - Walunas, Theresa L.

AU - Glessner, Joseph

AU - Hakonarson, Hakon

AU - Cox, Nancy J.

AU - Roden, Dan M.

AU - Frangakis, Stephan G.

AU - Vanderwerff, Brett

AU - Stein, C. Michael

AU - Van Driest, Sara L.

AU - Borinstein, Scott C.

AU - Shu, Xiao Ou

AU - Zawistowski, Matthew

AU - Chung, Cecilia P.

AU - Kawai, Vivian K.

PY - 2024/12

Y1 - 2024/12

N2 - Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30−0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69−0.88], p = 4.0 × 10−5) or immunosuppressant (n = 354, HR = 0.61 [0.38–0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44−0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

AB - Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30−0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69−0.88], p = 4.0 × 10−5) or immunosuppressant (n = 354, HR = 0.61 [0.38–0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44−0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

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Clinical associations with a polygenic predisposition to benign lower white blood cell counts

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