The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45 0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39 0.76]). The single new locus identified in our study is defined by a rare p.Arg172- Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.
Mousas A, Ntritsos G, Chen M-H, Song C, Huffman JE, Tzoulaki I, et al. (2017). Rare coding variants pinpoint genes that control human hematological traits.
Genetics of blood-cell traits
The proliferation and differentiation of hematopoietic progenitor cells into mature blood cells is a tightly regulated process. Red blood cell (RBC), white blood cell (WBC) and platelet counts are used in medicine as biomarkers to monitor general health status, to diagnose diseases, and as prognostic indicators of various clinical disorders. The goals of our study are: (1) to identify novel genetic variants associated with blood-cell trait variation in the UK Biobank participants and (2) test if these genetic variants also associate with cardiovascular diseases, including stroke. Variation in blood-cell traits is observed in various human diseases (e.g. cancer) and is used as predictive marker for heart diseases and stroke. Our project will explore the genetic contribution to inter-individual blood-cell variation, and test whether these genetic factors also influence our risk of heart diseases and stroke. The number and features of the main blood cells (red blood cells, white blood cells, and platelets) have been measured in all UK Biobank participants. Similarly, the DNA of all UK Biobank participants will be genotyped on the UK Biobank Affymetrix array. We propose to test the correlation between genotypes and inter-individual variation in blood-cell traits using standard genetic association methodologies. When appropriate, we will control blood-cell variables with potential confounders (such as sex, age, cancer status, infectious disease status, kidney or liver disease, etc.). Full cohort.
|Lead investigator:||Professor Guillaume Lettre|
|Lead institution:||Montreal Heart Institute|
1 related Return
|Return ID||App ID||Description||Archive Date|
|777||11707||An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility||17 Oct 2017|
|777||Rare coding variants pinpoint genes that control human hematological traits||Mousas A et al.||2017||PLoS Genet|