Mousas Abdou, Ntritsos Georgios, Chen Ming-Huei, Song Ci, Huffman Jennifer E, Tzoulaki Ioanna, Elliott Paul, Psaty Bruce M, Auer Paul L, Johnson Andrew D, Evangelou Evangelos, Lettre Guillaume, Reiner Alexander P
Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
Montreal Heart Institute, Montréal, Québec, Canada.
PLoS Genet. 2017 Aug 7;13(8):e1006925. doi: 10.1371/journal.pgen.1006925. eCollection 2017 Aug.
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.Arg172Gly 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.
识别罕见的编码或剪接位点变异仍然是将基因与人类表型联系起来的最直接策略。在此，我们分析了多达308,572名参与者中137,086个罕见（次要等位基因频率[MAF]<1%）编码或剪接位点变异与15种血液学性状之间的关联。我们在P<5×10⁻⁸时发现了56个此类罕见编码或剪接位点变异，其中31个是首次与血细胞表型相关联。这31个新的独立变异中，除了一个之外，其余均映射到先前全基因组关联研究（GWAS）中涉及造血作用的位点。这包括白细胞介素33（IL33）中的一个罕见剪接受体变异（rs146597587，MAF = 0.5%），与嗜酸性粒细胞计数降低相关（P = 2.4×10⁻²³），以及哮喘风险降低（P = 2.6×10⁻⁷，优势比[95%置信区间]= 0.56 [0.45 - 0.70]）和过敏性鼻炎风险降低（P = 4.2×10⁻⁴，优势比 = 0.55 [0.39 - 0.76]）。我们研究中确定的单个新位点由纤溶酶原（PLG）中的一个罕见的p.Arg172Gly错义变异（rs145535174，MAF = 0.05%）定义，该变异与血小板计数增加相关（P = 6.8×10⁻⁹），D - 二聚体浓度降低（P = 0.018）以及血小板反应性降低（P<0.03）。最后，我们的结果表明，在非常大的样本量中搜索罕见的编码或剪接位点变异有助于在许多与复杂人类疾病和性状相关的GWAS位点上确定因果基因的优先级。
