Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases
Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases
复制标题
白色血细胞性状和多效性与免疫介导疾病的大规模外显子组全关联分析
DOI：
10.1016/j.ajhg.2016.05.003
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发表时间：
2016-07-07
影响因子：
9.8
通讯作者：
Auer, Paul L.
中科院分区：
文献类型：
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作者：
Tajuddin, Salman M.;Schick, Ursula M.;Auer, Paul L.
白色血细胞在先天免疫和适应性免疫中发挥着不同的作用。对来自健康个体的大样本的循环白色血细胞（WBC）计数中的表型变异的遗传关联分析可以提供对涉及特定WBC谱系（骨髓、淋巴）的产生、分化或清除的基因和生物学途径的见解，并且还可能告知自身免疫性、过敏性和血液疾病的遗传基础。我们对来自25项研究的157，622例多血统发现和复制样本中的总WBC和亚型计数（中性粒细胞，单核细胞，淋巴细胞，嗜碱性粒细胞和嗜酸性粒细胞）进行了基于外显子组阵列的荟萃分析。我们鉴定了16种与一种或多种WBC性状相关的常见变异（其中8种为编码变异），其中大多数与自身免疫性疾病多效性相关。基于功能注释，这些基因座包括编码髓样、淋巴样或造血干细胞分化的表面标记的基因（CD 69，CD 33，CD 87），造血过程中调节谱系特化的转录因子（ASXL 1、IRF 8、IKZF 1、JMJD 1C、ETS 2-PSMG 1）和参与中性粒细胞清除/凋亡的分子（C10 orf 54，LTA），粘附（TNXB），或中心体和微管结构/功能（KIF 9，TUBD 1）。与最近报道的在具有未确定意义的特发性血细胞减少症或克隆性造血的个体中的体细胞ASXL 1突变一起，ASXL 1的常见调节性3 ' UTR变体的鉴定表明生殖系和体细胞ASXL 1突变都有助于在其他无症状个体中降低血细胞计数。这些关联结果揭示了调节循环WBC计数的遗传机制，并表明炎症和自身免疫性疾病具有显著的共享遗传结构。
White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of similar to 157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3 ' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.