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Blood Cell Traits Linked to Individual Loci, Polygenic Contributors in International Studies

NEW YORK – In a pair of new studies, international research teams have tracked down genetic contributors to blood cell traits, which may offer clues to everything from normal hematopoiesis to anemia, hemophilia, clotting conditions, blood cancer, and related common diseases.

For the first of the studies, published in Cell on Thursday, a team led by investigators at the Wellcome Sanger Institute, University of Cambridge, Dana-Farber Cancer Institute, and the Broad Institute presented findings from a genome-wide association study that involved more than 563,000 individuals of European descent, including 408,112 UK Biobank participants assessed for 29 blood cell phenotypes and analyses focused on 15 blood cell-related features in nearly 155,000 more individuals enrolled through the Blood Cell Consortium study.

The researchers unearthed more than 7,100 variants with independent ties to more than two-dozen blood cell features, including 5,106 variants not implicated in these phenotypes in the past. From there, they delved into the genetic architecture of these contributors, uncovering a combination of single-gene and polygenic variants behind these features.

Along with individual genes implicated in blood traits, the team's data suggested that a web of polygenic variants appeared to mediate and modulate those blood traits, influencing the penetrance of monogenic conditions, the expressivity of blood cell-related diseases, and more.

"[W]e have been able to show how a person's genetic predisposition to certain blood-related measurements, as indicated by their polygenic score, can predispose them to blood disease," co-first author Dragana Vuckovic, a human genetics researcher affiliated with the Wellcome Sanger Institute and University of Cambridge, said in a statement issued by the Sanger Institute.

Those polygenic scores appeared to get a performance boost through analyses that looked at specific subsets of variants with related genetic associations, co-first author Parsa Akbari, a public health, biostatistics, cardiovascular, and human genetics researcher affiliated with the University of Cambridge and the Sanger Institute, explained in a statement.

More broadly, Vuckovic, Akbari, and their co-authors suggested that the new results "provide a novel framework for considering an individual's genetic background and how this may impact the presentation of blood diseases."

For a related paper appearing in Cell on Thursday, researchers from the US, Canada, Japan, and the UK provided a broader look at the genetics of blood cell features in populations with European, East Asian, African, Hispanic/Latino, and South Asian ancestry, with a meta-analysis that included data for nearly 750,000 individuals and 15 phenotypes reflecting red blood cell, white blood cell, or platelet features.

That cross-ancestry analysis uncovered 5,552 apparent associations between genetic variants and blood cell traits in one or more population. That set encompassed roughly 100 variant associations that were specific to non-European populations, including variants falling at 71 genetic loci that have not been linked to blood traits in the past.

The team went on to consider everything from genetic architecture and fine-mapping patterns to functional effects of the variants identified and potential selection signals. It also did "phenome-wide" association studies in three of the ancestry groups considered, using biobank data for hundreds of thousands of individuals with European, Japanese, or African-American ancestry, and considered polygenic scores corresponding to various blood cell traits. 

"We continued to expand the repertoire of loci and genes that contribute to interindividual variation in blood cell traits, with potential implications for hematological diseases as well as other conditions, such as cancer and immune and cardiovascular diseases," the authors reported, adding that "because of heterogeneity across populations in allele frequencies and patterns of [linkage disequilibrium], fine-mapping of association signal of association signals can be substantially aided by including multiple ancestries."