Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Hum Mol Genet. 2019 Dec 1;28(23):4022-4041. doi: 10.1093/hmg/ddz175.
Even though heritability estimates suggest that the risk of asthma, hay fever and eczema is largely due to genetic factors, previous studies have not explained a large part of the genetics behind these diseases. In this genome-wide association study, we include 346 545 Caucasians from the UK Biobank to identify novel loci for asthma, hay fever and eczema and replicate novel loci in three independent cohorts. We further investigate if associated lead single nucleotide polymorphisms (SNPs) have a significantly larger effect for one disease compared to the other diseases, to highlight possible disease-specific effects. We identified 141 loci, of which 41 are novel, to be associated (P ≤ 3 × 10-8) with asthma, hay fever or eczema, analyzed separately or as disease phenotypes that includes the presence of different combinations of these diseases. The largest number of loci was associated with the combined phenotype (asthma/hay fever/eczema). However, as many as 20 loci had a significantly larger effect on hay fever/eczema only compared to their effects on asthma, while 26 loci exhibited larger effects on asthma compared with their effects on hay fever/eczema. At four of the novel loci, TNFRSF8, MYRF, TSPAN8, and BHMG1, the lead SNPs were in Linkage Disequilibrium (LD) (>0.8) with potentially casual missense variants. Our study shows that a large amount of the genetic contribution is shared between the diseases. Nonetheless, a number of SNPs have a significantly larger effect on one of the phenotypes, suggesting that part of the genetic contribution is more phenotype specific.
尽管遗传率估计表明，哮喘、花粉症和湿疹的风险在很大程度上是由于遗传因素，但之前的研究并没有解释这些疾病背后的大部分遗传原因。在这项全基因组关联研究中，我们纳入了来自英国生物库的 346545 名白种人，以确定哮喘、花粉症和湿疹的新基因座，并在三个独立队列中复制新基因座。我们进一步研究了与疾病相关的先导单核苷酸多态性（SNP）是否对一种疾病的影响明显大于其他疾病，以突出可能存在的疾病特异性影响。我们确定了 141 个与哮喘、花粉症或湿疹（单独或作为包含这些疾病不同组合的疾病表型）相关的基因座（P≤3×10-8），其中 41 个是新的。与联合表型（哮喘/花粉症/湿疹）相关的基因座数量最多。然而，多达 20 个基因座对花粉症/湿疹的影响明显大于对哮喘的影响，而 26 个基因座对哮喘的影响大于对花粉症/湿疹的影响。在四个新基因座（TNFRSF8、MYRF、TSPAN8 和 BHMG1）中，先导 SNP 与潜在的致病错义变体处于连锁不平衡（LD）（>0.8）。我们的研究表明，这些疾病之间存在大量遗传贡献的共享。尽管如此，一些 SNP 对一种表型的影响明显更大，这表明部分遗传贡献更具有表型特异性。
