Department of Medicine, The University of Chicago, Chicago, IL, USA.
Department of Medicine, The University of Chicago, Chicago, IL, USA; Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
Lancet Respir Med. 2019 Jun;7(6):509-522. doi: 10.1016/S2213-2600(19)30055-4. Epub 2019 Apr 27.
Childhood-onset and adult-onset asthma differ with respect to severity and comorbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated in large samples. The goals of this study were to identify shared and distinct genetic risk loci for childhood-onset and adult-onset asthma, and to identify the genes that might mediate the effects of associated variation.
We did genome-wide and transcriptome-wide studies, using data from the UK Biobank, in individuals with asthma, including adults with childhood-onset asthma (onset before 12 years of age), adults with adult-onset asthma (onset between 26 and 65 years of age), and adults without asthma (controls; aged older than 38 years). We did genome-wide association studies (GWAS) for childhood-onset asthma and adult-onset asthma each compared with shared controls, and for age of asthma onset in all asthma cases, with a genome-wide significance threshold of p<5 × 10. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes.
Of 376 358 British white individuals from the UK Biobank, we included 37 846 with self-reports of doctor-diagnosed asthma: 9433 adults with childhood-onset asthma; 21 564 adults with adult-onset asthma; and an additional 6849 young adults with asthma with onset between 12 and 25 years of age. For the first and second GWAS analyses, 318 237 individuals older than 38 years without asthma were used as controls. We detected 61 independent asthma loci: 23 were childhood-onset specific, one was adult-onset specific, and 37 were shared. 19 loci were associated with age of asthma onset. The most significant asthma-associated locus was at 17q12 (odds ratio 1·406, 95% CI 1·365-1·448; p=1·45 × 10) in the childhood-onset GWAS. Genes at the childhood onset-specific loci were most highly expressed in skin, blood, and small intestine; genes at the adult onset-specific loci were most highly expressed in lung, blood, small intestine, and spleen. PrediXcan identified 113 unique candidate genes at 22 of the 61 GWAS loci. Single-nucleotide polymorphism-based heritability estimates were more than three times larger for childhood-onset asthma (0·327) than for adult-onset disease (0·098). The onset of disease in childhood was associated with additional genes with relatively large effect sizes, with the largest odds ratio observed at the FLG locus at 1q21.3 (1·970, 95% CI 1·823-2·129).
Genetic risk factors for adult-onset asthma are largely a subset of the genetic risk for childhood-onset asthma but with overall smaller effects, suggesting a greater role for non-genetic risk factors in adult-onset asthma. Combined with gene expression and tissue enrichment patterns, we suggest that the establishment of disease in children is driven more by dysregulated allergy and epithelial barrier function genes, whereas the cause of adult-onset asthma is more lung-centred and environmentally determined, but with immune-mediated mechanisms driving disease progression in both children and adults.
US National Institutes of Health.
儿童期和成年期哮喘在严重程度和合并症方面存在差异。它们在遗传风险因素方面是否也存在差异，此前尚未在大样本中进行过研究。本研究的目的是确定儿童期和成年期哮喘的共享和独特的遗传风险位点，并确定可能介导相关变异影响的基因。
我们使用英国生物库中的个体数据进行了全基因组和全转录组研究，包括患有哮喘的成年人，包括儿童期哮喘（发病年龄<12 岁）的成年人、成年期哮喘（发病年龄 26-65 岁）的成年人和无哮喘的成年人（对照组；年龄>38 岁）。我们对儿童期哮喘和成年期哮喘分别进行了全基因组关联研究（GWAS），并与共享对照组进行了比较，还对所有哮喘病例的发病年龄进行了 GWAS，全基因组显著性阈值为 p<5 × 10。富集研究确定了 GWAS 位点中基因在哪些组织中表达水平最高，转录组全基因预测分析（PrediXcan）用于鉴定候选风险基因。
在英国生物库的 376 358 名英国白人个体中，我们纳入了 37 846 名有医生诊断为哮喘的个体：9433 名成年期儿童哮喘患者；21 564 名成年期成人哮喘患者；另外还有 6849 名发病年龄在 12-25 岁之间的年轻成年人哮喘患者。对于第一项和第二项 GWAS 分析，我们使用了 318 237 名年龄大于 38 岁且无哮喘的个体作为对照组。我们检测到 61 个独立的哮喘位点：23 个是儿童期特有的，1 个是成年期特有的，37 个是共享的。19 个位点与哮喘发病年龄相关。最显著的哮喘相关位点是在 17q12（优势比 1·406，95%CI 1·365-1·448；p=1·45 × 10）在儿童期哮喘的 GWAS 中。儿童期发病特异性位点的基因在皮肤、血液和小肠中表达水平最高；成年期发病特异性位点的基因在肺、血液、小肠和脾脏中表达水平最高。PrediXcan 在 61 个 GWAS 位点中的 22 个位点鉴定出 113 个独特的候选基因。儿童期哮喘的单核苷酸多态性遗传率估计值（0·327）是成年期疾病（0·098）的三倍多。疾病在儿童期发病与相对较大效应大小的其他基因有关，在 1q21.3 上的 FLG 基因观察到最大的比值比（1·970，95%CI 1·823-2·129）。
成人期哮喘的遗传风险因素在很大程度上是儿童期哮喘遗传风险因素的一个子集，但总体影响较小，这表明非遗传风险因素在成人期哮喘中起着更大的作用。结合基因表达和组织富集模式，我们认为儿童发病是由过敏和上皮屏障功能基因失调驱动的，而成年期哮喘的病因则更集中在肺部，与环境有关，但免疫介导的机制在儿童和成人中都驱动着疾病的进展。
美国国立卫生研究院。
