Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program,American Journal of Human Genetics

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Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2021-09-27 , DOI: 10.1016/j.ajhg.2021.08.007
Anna V Mikhaylova ₁ , Caitlin P McHugh ₁ , Linda M Polfus ₂ , Laura M Raffield ₃ , Meher Preethi Boorgula ₄ , Thomas W Blackwell ₅ , Jennifer A Brody ₆ , Jai Broome ₁ , Nathalie Chami ₇ , Ming-Huei Chen ₈ , Matthew P Conomos ₁ , Corey Cox ₄ , Joanne E Curran ₉ , Michelle Daya ₄ , Lynette Ekunwe ₁₀ , David C Glahn ₁₁ , Nancy Heard-Costa ₁₂ , Heather M Highland ₁₃ , Brian D Hobbs ₁₄ , Yann Ilboudo ₁₅ , Deepti Jain ₁ , Leslie A Lange ₄ , Tyne W Miller-Fleming ₁₆ , Nancy Min ₁₀ , Jee-Young Moon ₁₇ , Michael H Preuss ₇ , Jonathon Rosen ₁₈ , Kathleen Ryan ₁₉ , Albert V Smith ₅ , Quan Sun ₁₈ , Praveen Surendran ₂₀ , Paul S de Vries ₂₁ , Klaudia Walter ₂₂ , Zhe Wang ₇ , Marsha Wheeler ₂₃ , Lisa R Yanek ₂₄ , Xue Zhong ₁₆ , Goncalo R Abecasis ₅ , Laura Almasy ₂₅ , Kathleen C Barnes ₄ , Terri H Beaty ₂₆ , Lewis C Becker ₂₇ , John Blangero ₉ , Eric Boerwinkle ₂₁ , Adam S Butterworth ₂₈ , Sameer Chavan ₄ , Michael H Cho ₂₉ , Hélène Choquet ₃₀ , Adolfo Correa ₁₀ , Nancy Cox ₁₆ , Dawn L DeMeo ₁₄ , Nauder Faraday ₃₁ , Myriam Fornage ₃₂ , Robert E Gerszten ₃₃ , Lifang Hou ₃₄ , Andrew D Johnson ₈ , Eric Jorgenson ₃₅ , Robert Kaplan ₁₇ , Charles Kooperberg ₃₆ , Kousik Kundu ₃₇ , Cecelia A Laurie ₁ , Guillaume Lettre ₁₅ , Joshua P Lewis ₁₉ , Bingshan Li ₃₈ , Yun Li ₃₉ , Donald M Lloyd-Jones ₄₀ , Ruth J F Loos ₇ , Ani Manichaikul ₄₁ , Deborah A Meyers ₄₂ , Braxton D Mitchell ₄₃ , Alanna C Morrison ₂₁ , Debby Ngo ₄₄ , Deborah A Nickerson ₂₃ , Suraj Nongmaithem ₂₂ , Kari E North ₁₃ , Jeffrey R O'Connell ₁₉ , Victor E Ortega ₄₅ , Nathan Pankratz ₄₆ , James A Perry ₄₇ , Bruce M Psaty ₄₈ , Stephen S Rich ₄₁ , Nicole Soranzo ₄₉ , Jerome I Rotter ₅₀ , Edwin K Silverman ₁₄ , Nicholas L Smith ₅₁ , Hua Tang ₅₂ , Russell P Tracy ₅₃ , Timothy A Thornton ₅₄ , Ramachandran S Vasan ₅₅ , Joe Zein ₅₆ , Rasika A Mathias ₅₇ , , Alexander P Reiner ₄₇ , Paul L Auer ₅₈

Affiliation

Department of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Division of Biomedical Informatics and Personalized Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
TOPMed Informatics Research Center, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98105, USA.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
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.
Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA.
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Department of Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston, MA 02155, USA.
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.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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.
Montréal Heart Institute, Montréal, Québec H1T 1C8, Canada; Faculté de Médecine, Université de Montréal, Montréal, Québec H1T 1C8, Canada.
Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, USA.
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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.
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.
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.
Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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.
School of Public Health, John Hopkins University, Baltimore, MD 21205, USA.
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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.
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Division of Research, Kaiser Permanente Northern California, Oakland, CA 94601, USA.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Institute for Public Health and Medicine, Northwestern University, Chicago, IL 60661, USA.
Regeneron Genetics Center, Tarrytown, NY 10591, USA.
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB1 8RN, UK.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
Departments of Biostatistics, Genetics, and Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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.
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA.
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.
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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.
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.
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.
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.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pathology and Laboratory Medicine and Department of Biochemistry, University of Vermont Larner College of Medicine, Colchester, VT 05446, USA.
Department of Biostatistics, University of Washington, Seattle, WA 98105, USA; Regeneron Genetics Center, Tarrytown, NY 10591, USA.
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.
Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Zilber School of Public Health, University of Wisconsin, Milwaukee, Milwaukee, WI 53205, USA.

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.

中文翻译：

不同受试者的全基因组测序确定了白细胞特征的遗传相关性：NHLBI TOPMed 程序

许多与血液学特征相关的常见和罕见变异已通过对大规模参考面板的插补发现。然而，大多数全基因组关联研究 (GWAS) 都是在欧洲人中进行的，确定因果变异已被证明具有挑战性。我们对精准医学跨组学 (TOPMed) 计划中常染色体和 X 染色体中的 109,563,748 个变异生成的总白细胞、中性粒细胞、淋巴细胞、单核细胞、嗜酸性粒细胞和嗜碱性粒细胞计数进行了 GWAS，其中包括来自 61,802 个个体的数据不同的血统。我们发现并复制了 7 种白细胞性状关联，包括 (1) X 染色体、拟常染色体区域 (PAR)、位于细胞因子受体基因 ( CSF2RA和CLRF2)和较低的嗜酸性粒细胞计数；(2) 主要在S1PR3 (9q22.1) 和HBB (11p15.4) 位点以及单核细胞和淋巴细胞计数的非裔美国人中发现的单一变异之间的关联。我们进一步提供的证据表明，新发现的嗜酸性粒细胞降低染色体 X PAR 变异可能与特应性皮炎和哮喘等常见过敏性疾病的易感性降低有关。此外，我们发现了与单核细胞计数相关的非常罕见的FLT3 (13q12.2) 变体的负担。总之，这些结果强调了不同样本中全基因组测序在识别欧洲血统驱动的 GWAS 遗漏的关联方面的效用。

更新日期：2021-10-09

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