Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10^-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (r_g = -0.63, P = 4.5x10^-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

导致过敏性疾病发病年龄个体间差异的风险因素知之甚少。本研究的目的是确定与过敏性疾病症状首次出现的年龄相关的遗传风险变异，同时考虑来自哮喘、花粉热和湿疹的信息。来自英国生物银行研究的 117,130 名欧洲血统的基因分型个体提供了自我报告的发病年龄信息。对于每个人，我们确定了首次诊断出哮喘、花粉热和/或湿疹的最早年龄，并对这种合并的发病年龄表型进行了全基因组关联研究 (GWAS)。我们确定了 50 个具有显着独立关联的变体 ( P <3x10 ^-8) 与发病年龄。在一项独立研究（ n = 222,484）中，45 种变体对三种单独疾病的发作具有相当的影响，38 种也与过敏性疾病病例对照状态相关。我们观察到发病年龄与过敏性疾病病例对照状态之间存在强烈的负遗传相关性（r _g = -0.63，P = 4.5x10 ^-61)，表明发病较早的病例比发病较晚的病例具有更大的过敏风险等位基因负担。随后，发病年龄和病例对照状态的多变量 GWAS 确定了另外 26 个关联，这些关联仅被发病年龄或病例对照状态的单变量分析遗漏。总的来说，在确定的 76 种变体中，18 种代表了过敏性疾病的新关联。我们根据来自表达数量性状基因座 (eQTL) 和非同义变体的信息确定了 76 个相关变体的 81 个可能的靶基因，其中我们突出显示ADAM15、FOSL2、TRIM8、BMPR2、CD200R1、PRKCQ、NOD2、SMAD4、ABCA7和UBE2L3。我们的结果支持这样一种观点，即早发性和迟发性过敏性疾病具有部分不同的遗传结构，这可能解释了个体之间已知的病理生理学差异。