Genetic Susceptibility to Pneumonia: A GWAS Meta-Analysis Between the UK Biobank and FinnGen
Genetic Susceptibility to Pneumonia: A GWAS Meta-Analysis Between the UK Biobank and FinnGen
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DOI：
10.1017/thg.2021.27
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发表时间：
2021-06-01
影响因子：
0.9
通讯作者：
Renteria, Miguel E.
中科院分区：
文献类型：
--
作者：
Campos, Adrian, I;Kho, Pik;Renteria, Miguel E.
肺炎是一种病因复杂的呼吸系统疾病。宿主遗传变异被认为是易感性和症状表现的个体差异的原因。在这里，我们分析了来自英国生物银行（14，780例病例和439，096例对照）和FinnGen（9980例病例和86，519例对照）的肺炎数据，并进行了全基因组关联研究荟萃分析。我们使用基于基因的测试，共定位，遗传相关性，潜在的因果变量（LCV）和多基因预测在一个独立的澳大利亚样本（N = 5595），以了解肺炎风险的病因。我们确定了15号染色体上两个独立的基因座（前导单核苷酸多态性rs 2009746和rs76474922）与肺炎相关（p < 5e-8）。基于基因的检测发现15、16和9号染色体上的18个基因，包括IL 127、PBX 3、ApoB受体（APOBR）和吸烟相关基因CHRNA 3/5，与肺炎有统计学相关性。我们观察了肺炎与心肺、精神和炎症相关性状之间的遗传相关性。LCV分析表明与心血管健康表型有很强的遗传因果关系。在一个独立样本中，肺炎的多基因风险评分显著预测了自我报告的肺炎，尽管效应量很小（OR = 1.11 95% CI [1.04，1.19]，p <0.05）。敏感性分析表明，15号染色体的关联是由吸烟史介导的，但16号和9号染色体的关联以及多基因预测对吸烟的调整是稳健的。总而言之，我们的研究结果突出了导致肺炎易感性个体差异的常见遗传变异、基因和潜在途径，并推进了我们对呼吸道医疗结果异质性背后的遗传因素的理解。
Pneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian sample (N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia (p < 5e-8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent sample, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p < .05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the associations in chromosomes 16 and 9, and polygenic prediction were robust to adjustment for smoking. Altogether, our results highlight common genetic variants, genes and potential pathways that contribute to individual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.