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 8.1 ) 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,

9} , Matthew P. Conomos ₁ , Corey Cox ₄ , Joanne E. Curran ₁₀ , Michelle Daya ₄ , Lynette Ekunwe ₁₁ , David C. Glahn ₁₂ , Nancy Heard-Costa _{9,

13} , Heather M. Highland ₁₄ , Brian D. Hobbs _{15,

16} , Yann Ilboudo _{17,

18}

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
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

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 计划

通过在大规模参考面板上进行插补，已经发现了许多与血液学特征相关的常见和罕见变异。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 Trans-Omics for Precision Medicine (TOPMed) 计划中的常染色体和 X 染色体中的 109,563,748 个变异产生的总白细胞、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 个白细胞特征关联，包括 (1) X 染色体、假常染色体区域 (PAR)、位于细胞因子受体基因之间的非编码变异 ( CSF2RA和CLRF2)和较低的嗜酸性粒细胞计数；(2) 分别在S1PR3 (9q22.1) 和HBB (11p15.4) 基因座以及单核细胞和淋巴细胞计数的非裔美国人中主要发现的单一变异之间的关联。我们进一步提供证据表明，新发现的降低嗜酸性粒细胞的染色体 X PAR 变异可能与降低对常见过敏性疾病（如特应性皮炎和哮喘）的易感性有关。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) 变异负担。总之，这些结果强调了全基因组测序在不同样本中的效用，用于识别欧洲血统驱动的 GWAS 遗漏的关联。

更新日期：2021-10-09

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