Seventy-five genetic loci influencing the human red blood cell

Abstract

Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

“…A few genome-scale chromatin mapping studies have highlighted the enrichment of GWAS SNPs in regulatory DNA elements, suggesting that many functional variants may affect gene regulation (28)(29)(30)(31). After performing computer analyses and studying the ENCODE data for the 9q22 locus, we selected three regions and four SNPs for experimental functional analyses in a thyroid cancer cell line and in unaffected thyroid tissue.…”

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

“…Future research is required to understand these regions and the event duration associated region near rs35424364 (with the pseudogenes CCDC162P and C6ORF183/LOC100996694). This region seems to be biologically active and is associated with red blood cell traits (60).…”

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…Not only can basic insight into hematopoiesis be gained from such studies, but these findings can provide insight into blood disorders. Common variation in RBC traits appears to be associated with variation in the clinical course of specific forms of anemia, such as β-thalassemia (47). There is likely a much greater contribution of such common variation to disease states than we currently appreciate.…”

“…For example, we identified variants altering the levels of cyclins D3 and A2, which have key roles in regulating the cell divisions that occur in the last stages of erythropoiesis before the cells prepare to enucleate and form mature RBCs (45,46). It should be noted that over 75 loci have been identified as associated with RBC and other blood cell traits (47), suggesting that there may be more opportunities to gain important new insight into regulators of erythropoiesis and hematopoiesis through more systematic studies. In addition, rare or low frequency genetic variation may underlie some of the common variation observed in blood cell traits and important insight into new regulators of hematopoiesis may be gained through studies of this kind of variation (Figure 1), particularly as large-scale genome or exome sequencing is performed in cohorts with blood traits ascertained.…”