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

Anna V Mikhaylova; Caitlin P McHugh; Linda M Polfus; Laura M Raffield; Meher Preethi Boorgula; Thomas W Blackwell; Jennifer A Brody; Jai Broome; Nathalie Chami; Ming-Huei Chen; Matthew P Conomos; Corey Cox; Joanne E Curran; Michelle Daya; Lynette Ekunwe; David C Glahn; Nancy Heard-Costa; Heather M Highland; Brian D Hobbs; Yann Ilboudo; Deepti Jain; Leslie A Lange; Tyne W Miller-Fleming; Nancy Min; Jee-Young Moon; Michael H Preuss; Jonathon Rosen; Kathleen Ryan; Albert V Smith; Quan Sun; Praveen Surendran; Paul S de Vries; Klaudia Walter; Zhe Wang; Marsha Wheeler; Lisa R Yanek; Xue Zhong; Goncalo R Abecasis; Laura Almasy; Kathleen C Barnes; Terri H Beaty; Lewis C Becker; John Blangero; Eric Boerwinkle; Adam S Butterworth; Sameer Chavan; Michael H Cho; Hélène Choquet; Adolfo Correa; Nancy Cox; Dawn L DeMeo; Nauder Faraday; Myriam Fornage; Robert E Gerszten; Lifang Hou; Andrew D Johnson; Eric Jorgenson; Robert Kaplan; Charles Kooperberg; Kousik Kundu; Cecelia A Laurie; Guillaume Lettre; Joshua P Lewis; Bingshan Li; Yun Li; Donald M Lloyd-Jones; Ruth J F Loos; Ani Manichaikul; Deborah A Meyers; Braxton D Mitchell; Alanna C Morrison; Debby Ngo; Deborah A Nickerson; Suraj Nongmaithem; Kari E North; Jeffrey R O'Connell; Victor E Ortega; Nathan Pankratz; James A Perry; Bruce M Psaty; Stephen S Rich; Nicole Soranzo; Jerome I Rotter; Edwin K Silverman; Nicholas L Smith; Hua Tang; Russell P Tracy; Timothy A Thornton; Ramachandran S Vasan; Joe Zein; Rasika A Mathias; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Alexander P Reiner; Paul L Auer

doi:10.1016/j.ajhg.2021.08.007

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

Am J Hum Genet. 2021 Oct 7;108(10):1836-1851. doi: 10.1016/j.ajhg.2021.08.007. Epub 2021 Sep 27.

Authors

Anna V Mikhaylova¹, Caitlin P McHugh¹, Linda M Polfus², Laura M Raffield³, Meher Preethi Boorgula⁴, Thomas W Blackwell⁵, Jennifer A Brody⁶, Jai Broome¹, Nathalie Chami⁷, Ming-Huei Chen⁸, Matthew P Conomos¹, Corey Cox⁴, Joanne E Curran⁹, Michelle Daya⁴, Lynette Ekunwe¹⁰, David C Glahn¹¹, Nancy Heard-Costa¹², Heather M Highland¹³, Brian D Hobbs¹⁴, Yann Ilboudo¹⁵, Deepti Jain¹, Leslie A Lange⁴, Tyne W Miller-Fleming¹⁶, Nancy Min¹⁰, Jee-Young Moon¹⁷, Michael H Preuss⁷, Jonathon Rosen¹⁸, Kathleen Ryan¹⁹, Albert V Smith⁵, Quan Sun¹⁸, Praveen Surendran²⁰, Paul S de Vries²¹, Klaudia Walter²², Zhe Wang⁷, Marsha Wheeler²³, Lisa R Yanek²⁴, Xue Zhong¹⁶, Goncalo R Abecasis⁵, Laura Almasy²⁵, Kathleen C Barnes⁴, Terri H Beaty²⁶, Lewis C Becker²⁷, John Blangero⁹, Eric Boerwinkle²¹, Adam S Butterworth²⁸, Sameer Chavan⁴, Michael H Cho²⁹, Hélène Choquet³⁰, Adolfo Correa¹⁰, Nancy Cox¹⁶, Dawn L DeMeo¹⁴, Nauder Faraday³¹, Myriam Fornage³², Robert E Gerszten³³, Lifang Hou³⁴, Andrew D Johnson⁸, Eric Jorgenson³⁵, Robert Kaplan¹⁷, Charles Kooperberg³⁶, Kousik Kundu³⁷, Cecelia A Laurie¹, Guillaume Lettre¹⁵, Joshua P Lewis¹⁹, Bingshan Li³⁸, Yun Li³⁹, Donald M Lloyd-Jones⁴⁰, Ruth J F Loos⁷, Ani Manichaikul⁴¹, Deborah A Meyers⁴², Braxton D Mitchell⁴³, Alanna C Morrison²¹, Debby Ngo⁴⁴, Deborah A Nickerson²³, Suraj Nongmaithem²², Kari E North¹³, Jeffrey R O'Connell¹⁹, Victor E Ortega⁴⁵, Nathan Pankratz⁴⁶, James A Perry⁴⁷, Bruce M Psaty⁴⁸, Stephen S Rich⁴¹, Nicole Soranzo⁴⁹, Jerome I Rotter⁵⁰, Edwin K Silverman¹⁴, Nicholas L Smith⁵¹, Hua Tang⁵², Russell P Tracy⁵³, Timothy A Thornton⁵⁴, Ramachandran S Vasan⁵⁵, Joe Zein⁵⁶, Rasika A Mathias⁵⁷; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Alexander P Reiner⁵⁸, Paul L Auer⁵⁹

Affiliations

¹ Department of Biostatistics, University of Washington, Seattle, WA 98105, USA.
² Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
⁵ TOPMed Informatics Research Center, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98105, USA.
⁷ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
⁸ Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA; National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA.
⁹ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA.
¹⁰ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹¹ Department of Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston, MA 02155, USA.
¹² National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
¹³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁴ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Montréal Heart Institute, Montréal, Québec H1T 1C8, Canada; Faculté de Médecine, Université de Montréal, Montréal, Québec H1T 1C8, Canada.
¹⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, USA.
¹⁷ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹⁸ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁹ Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
²⁰ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB1 8RN, UK; Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
²¹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
²² Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.
²³ Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
²⁴ Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁵ Department of Biomedical and Health Informatics, the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
²⁶ School of Public Health, John Hopkins University, Baltimore, MD 21205, USA.
²⁷ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁸ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB1 8RN, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge CB1 8RN, UK.
²⁹ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³⁰ Division of Research, Kaiser Permanente Northern California, Oakland, CA 94601, USA.
³¹ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³² University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
³³ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³⁴ Institute for Public Health and Medicine, Northwestern University, Chicago, IL 60661, USA.
³⁵ Regeneron Genetics Center, Tarrytown, NY 10591, USA.
³⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
³⁷ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB1 8RN, UK.
³⁸ Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
³⁹ Departments of Biostatistics, Genetics, and Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴⁰ Division of Cardiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60661, USA; Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60661, USA.
⁴¹ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
⁴² Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA.
⁴³ Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA.
⁴⁴ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴⁵ Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
⁴⁶ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
⁴⁷ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁴⁸ Department of Epidemiology, University of Washington, Seattle, WA 98105, USA; Department of Health Service, University of Washington, Seattle, WA 98105, USA; Department of Medicine, University of Washington, Seattle, WA 98105, USA.
⁴⁹ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; Department of Haematology, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge CB1 8RN, UK.
⁵⁰ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
⁵¹ Department of Epidemiology, University of Washington, Seattle, WA 98105, USA; Department of Health Service, University of Washington, Seattle, WA 98105, USA; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA 98105, USA.
⁵² Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵³ Department of Pathology and Laboratory Medicine and Department of Biochemistry, University of Vermont Larner College of Medicine, Colchester, VT 05446, USA.
⁵⁴ Department of Biostatistics, University of Washington, Seattle, WA 98105, USA; Regeneron Genetics Center, Tarrytown, NY 10591, USA.
⁵⁵ National Heart, Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA; Departments of Cardiology and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA.
⁵⁶ Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁵⁷ Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵⁸ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: apreiner@uw.edu.
⁵⁹ Zilber School of Public Health, University of Wisconsin, Milwaukee, Milwaukee, WI 53205, USA. Electronic address: pauer@mcw.edu.

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.

Keywords: blood-cell counts; whole-genome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Asthma / epidemiology*
Asthma / genetics
Asthma / metabolism
Asthma / pathology
Biomarkers / metabolism*
Dermatitis, Atopic / epidemiology*
Dermatitis, Atopic / genetics
Dermatitis, Atopic / metabolism
Dermatitis, Atopic / pathology
Genetic Predisposition to Disease
Genome, Human
Genome-Wide Association Study
Humans
Leukocytes / pathology*
National Heart, Lung, and Blood Institute (U.S.)
Phenotype
Polymorphism, Single Nucleotide*
Prognosis
Proteome / analysis
Proteome / metabolism
Pulmonary Disease, Chronic Obstructive / epidemiology*
Pulmonary Disease, Chronic Obstructive / genetics
Pulmonary Disease, Chronic Obstructive / metabolism
Pulmonary Disease, Chronic Obstructive / pathology
Quantitative Trait Loci*
United Kingdom / epidemiology
United States / epidemiology
Whole Genome Sequencing

Substances

Biomarkers
Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding