Analysis of Rare Coding Variants in 470,000 UK Biobank Participants Reveals Genetic Associations With Childhood Asthma Predisposition

IF 2.3 4区 医学 Q3 GENETICS & HEREDITY
Zhenzhen Liu, David Curtis
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引用次数: 0

Abstract

Previous studies of genetic contributions to risk of childhood asthma have implicated common variants with small effect sizes. Some studies using exome sequence data have reported associations with rare coding variants having larger effects on risk, notably an analysis of 145,000 subjects which found association with loss of function (LOF) variants in FLG, the gene coding for filaggrin. Here, we report the results of an analysis of rare nonsynonymous and LOF variants, carried out on the full UK Biobank cohort of 470,000 exome-sequenced participants. The phenotype of childhood asthma was defined as reporting asthma with onset before 18. Regression analysis was applied to gene-wise tests for association of LOF and nonsynonymous variants. Forty-five tests using different pathogenicity predictors were applied to the first cohort of 200,000 participants. Subsequently, the 100 genes showing strongest evidence for association were analysed in the second cohort of 270,000 participants, using only the best-performing predictor for each gene. For FLG, separate analyses were carried out for participants with atopic dermatitis. Three genes achieved statistical significance after correction for testing these 100 genes: FLG, IL33 and PRKCQ. The effects on asthma risk and frequencies of variants in different functional categories were characterised for these genes. Damaging coding variants were associated with increased risk of asthma in FLG and IL33 but reduced risk in PRKCQ. FLG LOF variants were also associated with the risk of atopic dermatitis, and their effect on asthma risk was higher in people who reported a diagnosis of atopic dermatitis. Rare coding variants in a small number of genes have important effects on asthma risk. Further study of individual variant effects might elucidate mechanisms of pathogenesis. This research has been conducted using the UK Biobank Resource.

对47万英国生物银行参与者的罕见编码变异分析揭示了与儿童哮喘易感性的遗传关联。
先前关于遗传对儿童哮喘风险的影响的研究表明,常见的变异具有较小的影响。一些使用外显子组序列数据的研究报告了与罕见编码变异的关联对风险的影响更大,值得注意的是,一项对145,000名受试者的分析发现了与FLG(聚丝蛋白的基因编码)的功能丧失(LOF)变异的关联。在这里,我们报告了罕见的非同义和LOF变异的分析结果,对英国生物银行的47万名外显子组测序参与者进行了分析。儿童哮喘的表型定义为报告18岁以前发病的哮喘。回归分析应用于LOF和非同义变异体的关联基因测试。使用不同致病性预测因子的45项测试应用于20万参与者的第一个队列。随后,研究人员在第二组27万名参与者中分析了100个表现出最强关联证据的基因,对每个基因只使用表现最好的预测因子。对于FLG,对患有特应性皮炎的参与者进行单独的分析。对这100个基因进行检测校正后,FLG、IL33和PRKCQ三个基因具有统计学意义。这些基因在不同功能类别中对哮喘风险和变异频率的影响被表征。破坏性编码变异与FLG和IL33哮喘风险增加相关,但与PRKCQ风险降低相关。FLG - LOF变异也与特应性皮炎的风险相关,并且在被诊断为特应性皮炎的人群中,它们对哮喘风险的影响更高。少数基因中的罕见编码变异对哮喘风险有重要影响。进一步研究个体变异效应可能有助于阐明发病机制。这项研究是利用英国生物银行资源进行的。
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来源期刊
CiteScore
4.70
自引率
0.00%
发文量
48
审稿时长
6-12 weeks
期刊介绍: The International Journal of Immunogenetics (formerly European Journal of Immunogenetics) publishes original contributions on the genetic control of components of the immune system and their interactions in both humans and experimental animals. The term ''genetic'' is taken in its broadest sense to include studies at the evolutionary, molecular, chromosomal functional and population levels in both health and disease. Examples are: -studies of blood groups and other surface antigens- cell interactions and immune response- receptors, antibodies, complement components and cytokines- polymorphism- evolution of the organisation, control and function of immune system components- anthropology and disease associations- the genetics of immune-related disease: allergy, autoimmunity, immunodeficiency and other immune pathologies- All papers are seen by at least two independent referees and only papers of the highest quality are accepted.
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