NEW YORK (GenomeWeb News) – In a study appearing online today in Nature, a large international research group led by investigators in the UK and Germany reports on 75 independent sites in the genome associated with red blood cell features or formation.
The researchers tracked down and verified the loci — including dozens that hadn't been linked to red blood cell traits in the past — through a genome-wide association meta-analysis and replication studies involving more than 135,000 individuals for whom information on hemoglobin concentrations or other red blood cell features were available.
Together, the new and known loci detected in the meta-analysis pointed the team in the direction of more than 120 genes with potential roles in red blood cell-related processes, including genes with apparent roles in red blood cell function in mice or fruit flies.
"These results support the view that genetic association studies identify sets of genes that are conserved in evolution across a wide range of species," Wellcome Trust Sanger Institute researcher Nicole Soranzo, the study's co-senior author, said in a statement. "This is exciting because it means that we can obtain extensive new insights into the genetics and biological pathway of human health by studying model organisms."
Previous research suggests that genetic factors contribute to the regulation of red blood cell formation and function, Soranzo and colleagues said, from the size and abundance of those cells to the levels of oxygen-carrying hemoglobin they contain. That further suggests that improved genetic knowledge of such processes could help in understanding blood disorders such as anemia.
For the current study, researchers began with a meta-analysis, looking for sites in the genome related to half a dozen red blood cell-related phenotypes using GWAS data for 62,553 individuals of European ancestry and 9,308 individuals of South Asian ancestry.
Following validation studies in another 63,506 individuals, the team was left with 75 red blood cell trait-associated regions in the genome, including 32 loci implicated in past studies and 43 new loci. Together, the researchers reported, these 75 sites seem to be involved in 156 distinct associations with various red blood cell-related phenotypes.
By looking at the identity, nature, and expression of genes found in and around the red blood cell-associated regions, researchers put together a list of 121 genes that may be affected by coding or regulatory variants within the linked loci.
To help guide that follow-up analysis, researchers used Illumina arrays to assess gene expression patterns in differentiating red blood cells, starting from hematopoietic stem cells obtained from cord blood. They also turned to formaldehyde-assisted isolation of regulatory element, or FAIRE, sequencing to find apparently active regulatory sequences in several red blood cell-related cell types.
Data from the Mouse Genome Informatics database suggested that at least 29 of the 121 human candidate genes contribute to red blood cell formation or other hematological phenotypes in mice, the team noted. These included genes whose loss leads to lower-than-usual red blood cell levels and anemia in the animal model.
"These observations made in mice make it highly likely that the remaining candidate genes about which there is no knowledge yet, are also important regulators of red blood cell formation in people," co-senior author Willem Ouwehand, a hematology researcher affiliated with the University of Cambridge and National Health Service Blood and Transplant, said in a statement.
Follow-up experiments in fruit flies — including RNA interference-based gene silencing experiments in fruit fly hemocyte cells — further supported the notion that the set of 121 candidate human genes is especially prone to involvement in red blood cell-related phenotypes.
Based on the regulatory and coding patterns they've found in human cells so far, those involved in the study say they have narrowed in on 41 regions in the human genome containing causal variants involved in such traits. Still, they add, additional research is needed to determine the full suite of causal variants contributing to red blood cell features — as well as their functional consequences.
"[D]espite our extensive GWAS, bioinformatic, and experimental data, the precise identities of the causal variants, regulatory regions, and genes remain to be determined," the study's authors concluded, adding that "definitive identification will require further detailed experimental evaluation."