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

• Published in: American journal of human genetics 2021-10, Vol.108 (10), p.1836-1851
• Main Authors: Mikhaylova, Anna V., McHugh, Caitlin P., Polfus, Linda M., Raffield, Laura M., Boorgula, Meher Preethi, Blackwell, Thomas W., Brody, Jennifer A., Broome, Jai, Chami, Nathalie, Chen, Ming-Huei, Conomos, Matthew P., Cox, Corey, Curran, Joanne E., Daya, Michelle, Ekunwe, Lynette, Glahn, David C., Heard-Costa, Nancy, Highland, Heather M., Hobbs, Brian D., Ilboudo, Yann, Jain, Deepti, Lange, Leslie A., Miller-Fleming, Tyne W., Min, Nancy, Moon, Jee-Young, Preuss, Michael H., Rosen, Jonathon, Ryan, Kathleen, Smith, Albert V., Sun, Quan, Surendran, Praveen, de Vries, Paul S., Walter, Klaudia, Wang, Zhe, Wheeler, Marsha, Yanek, Lisa R., Zhong, Xue, Abecasis, Goncalo R., Almasy, Laura, Barnes, Kathleen C., Beaty, Terri H., Becker, Lewis C., Blangero, John, Boerwinkle, Eric, Butterworth, Adam S., Chavan, Sameer, Cho, Michael H., Choquet, Hélène, Correa, Adolfo, Cox, Nancy, DeMeo, Dawn L., Faraday, Nauder, Fornage, Myriam, Gerszten, Robert E., Hou, Lifang, Johnson, Andrew D., Jorgenson, Eric, Kaplan, Robert, Kooperberg, Charles, Kundu, Kousik, Laurie, Cecelia A., Lettre, Guillaume, Lewis, Joshua P., Li, Bingshan, Li, Yun, Lloyd-Jones, Donald M., Loos, Ruth J.F., Manichaikul, Ani, Meyers, Deborah A., Mitchell, Braxton D., Morrison, Alanna C., Ngo, Debby, Nickerson, Deborah A., Nongmaithem, Suraj, North, Kari E., O’Connell, Jeffrey R., Ortega, Victor E., Pankratz, Nathan, Perry, James A., Psaty, Bruce M., Rich, Stephen S., Soranzo, Nicole, Rotter, Jerome I., Silverman, Edwin K., Smith, Nicholas L., Tang, Hua, Tracy, Russell P., Thornton, Timothy A., Vasan, Ramachandran S., Zein, Joe, Mathias, Rasika A., Reiner, Alexander P., Auer, Paul L.
• Format: Article
• Language: English
• Subjects: Asthma - epidemiology; Asthma - genetics; Asthma - metabolism; Asthma - pathology; Biomarkers - metabolism; blood-cell counts; 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
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2021.08.007

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.