Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct
Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct
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DOI：
10.1016/j.ajhg.2019.02.022
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发表时间：
2019-04-04
影响因子：
9.8
通讯作者：
Almqvist, Catarina
中科院分区：
文献类型：
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作者：
Ferreira, Manuel A. R.;Mathur, Riddhima;Almqvist, Catarina
儿童期发作（COA）和成人发作（AOA）哮喘之间遗传风险因素的共享程度尚未估计。根据英国生物库研究（n = 447，628）的数据，我们发现常见变异解释的疾病易感性的方差对于COA（发病年龄在0至19岁之间; h（g）（2）= 25.6%）高于AOA（发病年龄在20至60岁之间; h（g）（2）= 10.6%）。COA与AOA的遗传相关系数r（g）为0.67。受COA影响的个体中发病年龄的变化具有较低的遗传力（h（g）（2）= 5%），我们在独立研究中以及受AOA影响的个体中证实了这一点。为了确定亚型特异性遗传关联，我们在英国生物库中对COA（13，962名受影响个体）进行了全基因组关联研究（GWAS），并通过使用两项研究的300，671名对照的共同集对AOA（26，582名受影响个体）进行了单独的GWAS。我们确定了COA的123个独立关联和AOA的56个独立关联（37个重叠）;其中分别有98个和34个在独立研究中可重复（n = 262，767）。总共有28个协会以前没有报告。对于96种COA相关变异，包括5种代表COA特异性风险因素的变异，风险等位基因在COA患者中比在AOA患者中更常见。相反，我们确定了三种变异是AOA的更强风险因素。与肥胖和吸烟相关的变异对AOA的风险比对COA的风险有更大的贡献。最后，我们确定了109个可能的相关变异的靶基因，主要是基于相关的表达数量性状基因座（n = 31，684）。根据发病年龄的GWAS可以识别亚型特异性风险变异，这可以帮助我们了解COA和AOA之间的病理生理学差异，因此可以为药物开发提供信息。
The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h(g)(2) = 25.6%) than for AOA (onset at ages between 20 and 60 years; h(g)(2) = 10.6%). The genetic correlation (r(g)) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h(g)(2) = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA-than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.