Background

Atopy, an endotype underlying allergic diseases, has a substantial genetic component.

Objective

Our goal was to identify novel genes associated with atopy in asthma-ascertained families.

Methods

We implemented a 3-step analysis strategy in 3 data sets: the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) data set (1660 subjects), the Saguenay-Lac-Saint-Jean study data set (1138 subjects), and the Medical Research Council (MRC) data set (446 subjects). This strategy included a single nucleotide polymorphism (SNP) genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results, and text-mining filtering using Gene Relationships Across Implicated Loci and SNP-SNP interaction analysis of selected gene pairs.

Results

We identified the 5q14 locus, harboring the adhesion G protein–coupled receptor V1 (ADGRV1) gene, which showed genome-wide significant association with atopy (rs4916831, meta-analysis P value = 6.8 × 10⁻⁹). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and 3 genes showing suggestive association with atopy (P ≤ 10⁻⁴). SNP-SNP interaction analysis between ADGRV1 and these 3 genes showed significant interaction between ADGRV1 rs17554723 and 2 correlated SNPs (rs2134256 and rs1354187) within the dynein axonemal heavy chain 5 (DNAH5) gene (P_meta-int = 3.6 × 10⁻⁵ and 6.1 × 10⁻⁵, which met the multiple-testing corrected threshold of 7.3 × 10⁻⁵). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723.

Conclusion

Because both DNAH5 and ADGRV1 contribute to ciliary function, this study suggests that ciliary dysfunction might represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying new genes involved in complex traits.

中文翻译：

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纤毛功能在特应性中的新作用：ADGRV1 和 DNAH5 相互作用

背景

特应性是过敏性疾病的一种内型，具有重要的遗传成分。

客观的

我们的目标是在哮喘确定的家族中鉴定与特应性相关的新基因。

方法

我们在 3 个数据集中实施了三步分析策略：哮喘遗传和环境流行病学研究 (EGEA) 数据集（1660 名受试者）、Saguenay-Lac-Saint-Jean 研究数据集（1138 名受试者）和医学研究委员会 (MRC) 数据集（446 名受试者）。该策略包括单核苷酸多态性 (SNP) 全基因组关联研究 (GWAS)、基于 GWAS 结果的统计过滤选择相关基因对，以及使用跨相关位点的基因关系和 SNP-SNP 相互作用分析的文本挖掘过滤选定的基因对。

结果

我们鉴定了 5q14 基因座，该基因座含有粘附 G 蛋白偶联受体 V1 ( ADGRV1 ) 基因，该基因显示全基因组与特应性显着相关（rs4916831，荟萃分析P值 = 6.8 × 10 ^-9）。GWAS 结果的统计过滤和文本挖掘过滤揭示了ADGRV1和 3 个基因之间的关系，显示出与特应性的暗示关联 ( P  ≤ 10 ^-4 )。ADGRV1与这 3 个基因之间的 SNP-SNP 相互作用分析显示ADGRV1 rs17554723 与动力蛋白轴突重链 5 (DNAH5)基因内的 2 个相关 SNP（rs2134256 和 rs1354187）之间存在显着的相互作用。P _meta-int  = 3.6 × 10 ^-5和 6.1 × 10 ^-5，满足多重测试校正阈值 7.3 × 10 ^-5）。进一步的条件分析表明，rs2134256 单独解释了与 rs17554723 的相互作用信号。

结论

因为 DNAH5 和 ADGRV1 都有助于纤毛功能，本研究表明纤毛功能障碍可能代表了一种新的特应性机制。将 GWAS 和由统计和基于知识的证据驱动的上位性分析相结合，代表了一种用于识别涉及复杂性状的新基因的有前景的方法。