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Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19
medRxiv - Genetic and Genomic Medicine Pub Date : 2020-10-06 , DOI: 10.1101/2020.10.05.20207118
Ana I. Hernández Cordero , Xuan Li , Stephen Milne , Chen Xi Yang , Yohan Bossé , Philippe Joubert , Wim Timens , Maarten van den Berge , David Nickle , Ke Hao , Don D. Sin

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We therefore used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n=1,038) and eQTLGen (n=31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n=3,301) with COVID-19-associated loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). We found that the expression of 20 genes in lung and 31 genes in blood was associated with COVID-19. Of these genes, only three (LZTFL1, SLC6A20 and ABO) had been previously linked with COVID-19 in GWAS. The novel loci included genes involved in interferon pathways (IL10RB, IFNAR2 and OAS1). Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in MR analysis; increased plasma levels were associated with an increased risk of having COVID-19 and risk of severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigation. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.

中文翻译:

多组学强调ABO血浆蛋白是COVID-19的致病危险因素

SARS-CoV-2负责2019年冠状病毒病(COVID-19)和当前的健康危机。尽管进行了深入的研究,但对COVID-19起作用的基因和途径仍知之甚少。因此,我们使用了整合基因组学(IG)方法来鉴定负责COVID-19及其严重性的候选基因。我们使用贝叶斯共定位(COLOC)和基于摘要的孟德尔随机化,将来自肺eQTL(n = 1,038)和eQTLGen(n = 31,784)研究的基因表达定量性状基因座(eQTL)与已发表的COVID-19全基因组关联研究相结合(GWAS)数据来自COVID-19主机遗传学计划。此外,我们使用COLOC将来自INTERVAL研究(n = 3,301)的血浆蛋白定量特征位点(pQTL)与COVID-19相关的位点整合在一起。最后,我们使用多变量两样本孟德尔随机(MR)确定了血浆蛋白与COVID-19之间的任何因果关系。我们发现肺中20个基因和血液中31个基因的表达与COVID-19相关。这些基因中,只有三个(LZTFL1,SLC6A20和ABO)先前与GWAS中的COVID-19相关。新的基因座包括与干扰素途径有关的基因(IL10RB,IFNAR2和OAS1)。血浆ABO蛋白与人类的血型有关,在MR分析中显示与COVID-19有显着的因果关系。血浆水平升高与罹患COVID-19的风险增加以及发生严重COVID-19的风险相关。总而言之,我们的研究确定了与COVID-19相关的基因,这些基因可能会在以后的研究中被优先考虑。重要的,
更新日期:2020-10-06
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