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New Leukocyte-Linked Loci Uncovered With Multi-Ancestry Genomes

NEW YORK – An international research team has detected new genetic loci involved in white blood cell traits using a whole-genome sequencing-based association study involving tens of thousands of individuals from a range of ancestral backgrounds.

"Our results … extend the clinical importance of variants underlying WBC count and immune-related quantitative traits, particularly to non-European populations," senior and co-corresponding author Paul Auer, a biostatistics researcher at the Medical College of Wisconsin, and his colleagues wrote in a study published in the American Journal of Human Genetics.

By bringing together whole-genome sequencing data for more than 61,800 individuals — including nearly 33,300 European American participants, more than 14,200 individuals of African American ancestry, 686 East Asians, and almost 13,600 individuals of Hispanic/Latino ancestry — members of the National Heart, Lung, and Blood Institute's "Trans-omics for Precision Medicine," or TOPMed, program did a genome-wide association study searching for variants associated with features in leukocytes, or white blood cells.

Investigators at Broad Genomics, the Northwest Genomics Center, Illumina, the New York Genome Center, Baylor, and the McDonnell Genome Institute did deep whole-genome sequencing on 61,802 TOPMed participants, generating sequences that covered the genome to 38-fold depth, on average.

When the team set the sequences alongside available data on concentrations of basophil, eosinophil, neutrophil, lymphocyte, monocyte, and total white blood cell counts in TOPMed blood samples, it identified nearly 109.6 million single nucleotide or small insertion/deletion variants that were used to search for genetic ties to half a dozen blood cell-related phenotypes.

From 165 associations found with a conditional analysis focused on white blood cell counts, the investigators narrowed in on 18 loci with independent ties to the leukocyte trait, including seven new loci in or around the CSF2RA, HBB, NRIP1, S1PR3, OPCML, and NPHP3 genes that were replicated in more than 199,100 individuals from European, European American, Hispanic American, or African American populations.

At the CSF2RA locus on the X chromosome, for example, the team dug down to find a variant in a so-called "pseudo-autosomal region" (PAR1) that appeared to be particularly common in individuals of African ancestry that was associated with dialed down eosinophil counts, along with lower-than-usual prevalence of allergic conditions.

Still other variants at the S1PR3 locus on chromosome 9 appeared to be associated with monocyte counts in the African American participants, the authors reported, while a missense mutation at a chromosome 11 locus containing HBB was linked to reduced lymphocyte levels and sickle-cell disease.

These and other findings "emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European ancestry-driven GWASs," they wrote, concluding that the "identification of monocyte-specific associations, including an African ancestry variant at the S1PR3 locus and a burden of very rare variants in FLT3, might warrant additional study in the context of infectious or autoimmune diseases, respectively."

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