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Red Blood Cell Traits Linked to New Loci With Whole-Genome Sequencing Data

NEW YORK – Investigators at the Fred Hutchinson Cancer Research Center, the University of Washington, and elsewhere have identified 12 new genetic loci with ties to red blood cell (RBC) features using a whole-genome sequencing study approach.

The team tapped into the National Heart, Lung, and Blood Institute's "Trans-omics for Precision Medicine" (TOPMed) program to get whole-genome sequencing data for nearly 62,700 individuals from European, African, Hispanic/Latino, and East Asian ancestry groups for an association study focused on coding and non-coding variants linked to seven quantitative RBC features. The findings, published in the American Journal of Human Genetics on Wednesday, revealed dozens of new or known loci with significant RBC associations — a set that included low-frequency alterations and RBC-related variants that were overrepresented in non-European individuals.

"The study highlights the utility of whole-genome sequence data from ethnically diverse populations using resources such as the NHLBI TOPMed project, as well as gene editing, for identifying population-specific genetic variants that may underlie hematologic disorders related to red blood cells," senior author Alexander Reiner, an epidemiologist at the University of Washington, said in an email.

For their analyses, the researchers considered whole-genome sequence data for 62,653 TOPMed participants from a range of ancestral groups, searching for variants linked to seven quantifiable RBC traits and conditions ranging from hemoglobin and hematocrit levels to RBC counts. Their search highlighted 14 significant associations involving rare or low-frequency variants at 12 loci, including eight loci validated using data from several existing genome-wide association study cohorts.

Among the associations, the team pointed to ties between mean corpuscular hemoglobin concentration and a deletion in the PIEZO1 gene that appeared to be relatively common in individuals with Ashkenazi Jewish ancestry. The same gene has been implicated in an RBC condition called hereditary xerocytosis in the past.

The team's association data and follow-up gene editing experiments also unearthed an association that appears to stem from a long-range regulatory element that affects RUVBL1, leading to lower-than-usual expression of the hematopoiesis-related gene.

In some cases, the researchers noted, the RBC phenotypes in question tracked with the "carrier," or heterozygous form of inherited RBC conditions that usually occur in those carrying homozygous or compound heterozygous versions of the variants. And with gene-based analyses, they flagged seven genes in which rare RBC-associated variants appeared to be overrepresented, including in the HBB, HBA1, and TMPRSS6 genes that showed ties to multiple RBC traits.

"The gene-based association of rare variants within HBA1/2, HBB, TMPRSS6, G6PD, CD36, TFRC, and SLC12A7 independent of known single variants in the same genes further suggest that rare functional variants in genes responsible for Mendelian RBC disorders contribute to the genetic architecture of RBC phenotypic variation among the population at large," the authors suggested.

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