Leveraging pleiotropy identifies common-variant associations with selective IgA deficiency

IF 4.5 3区 医学 Q2 IMMUNOLOGY Clinical immunology Pub Date : 2024-09-04 DOI:10.1016/j.clim.2024.110356
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Abstract

Selective IgA deficiency (SIgAD) is the most common inborn error of immunity (IEI). Unlike many IEIs, evidence of a role for highly penetrant rare variants in SIgAD is lacking. Previous SIgAD studies have had limited power to identify common variants due to their small sample size. We overcame this problem first through meta-analysis of two existing GWAS. This identified four novel common-variant associations and enrichment of SIgAD-associated variants in genes linked to Mendelian IEIs. SIgAD showed evidence of shared genetic architecture with serum IgA and a number of immune-mediated diseases. We leveraged this pleiotropy through the conditional false discovery rate procedure, conditioning our SIgAD meta-analysis on large GWAS of asthma and rheumatoid arthritis, and our own meta-analysis of serum IgA. This identified an additional 18 variants, increasing the number of known SIgAD-associated variants to 27 and strengthening the evidence for a polygenic, common-variant aetiology for SIgAD.

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利用多态性确定选择性 IgA 缺乏症的共变体关联。
选择性 IgA 缺乏症(SIgAD)是最常见的先天性免疫错误(IEI)。与许多先天性免疫缺陷(IEI)不同,目前还没有证据表明高渗透性罕见变异在 SIgAD 中起作用。以往的 SIgAD 研究由于样本量小,识别常见变异的能力有限。我们首先通过对现有的两项全球基因组研究进行荟萃分析,克服了这一问题。这发现了四个新的共同变异关联,并在与孟德尔IEIs相关的基因中富集了SIgAD相关变异。有证据表明,SIgAD 与血清 IgA 和一些免疫介导疾病具有共同的遗传结构。我们通过条件假发现率程序利用了这一多向性,将哮喘和类风湿性关节炎的大型 GWAS 以及我们自己对血清 IgA 的荟萃分析作为 SIgAD 荟萃分析的条件。这又发现了 18 个变体,使已知的 SIgAD 相关变体增加到 27 个,从而加强了 SIgAD 多基因、共变体病因学的证据。
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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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