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.
To analyse the blood-cell traits and test their association with genotypes using standard genetic association methodologies.
To study the genetics of these quantitative blood traits may reveal new biologic pathways that ultimately not only (1) contribute to our understanding of hematopoiesis but also (2) provide new avenues for treatment of patients with low or high blood counts, and (3) illuminate new mechanisms of association of high or low blood counts with chronic inflammatory and thrombotic diseases.
1. Samuel Lessard, et al. An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility
2. 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.
|Lead investigator:||Guillaume Lettre|
|Lead institution:||Montreal Heart Institute|