Genetic architecture of host proteins involved in SARS-CoV-2 infection.
Genetic architecture of host proteins involved in SARS-CoV-2 infection.
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与SARS-COV-2感染有关的宿主蛋白的遗传结构。
DOI：
10.1038/s41467-020-19996-z
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发表时间：
2020-12-16
影响因子：
16.6
通讯作者：
Langenberg C
中科院分区：
文献类型：
--
作者：
Pietzner M;Wheeler E;Carrasco-Zanini J;Raffler J;Kerrison ND;Oerton E;Auyeung VPW;Luan J;Finan C;Casas JP;Ostroff R;Williams SA;Kastenmüller G;Ralser M;Gamazon ER;Wareham NJ;Hingorani AD;Langenberg C
了解宿主蛋白与SARS-CoV-2相互作用或介导宿主对COVID-19的不适应反应的遗传结构，有助于识别针对这些蛋白的新药物或重新利用现有药物。我们使用基于适配体的技术对10,708个个体中的179个这样的宿主蛋白进行了遗传发现研究。我们鉴定了220个宿主DNA序列变异，作用于顺式（MAF 0.01-49.9%），并解释了其中97个蛋白质变异的0.3-70.9%，其中45个以前没有已知的蛋白质数量性状位点（pQTL）， 38个编码当前药物靶点。通过现象组对pqtl进行系统表征，确定了蛋白质-药物-疾病联系，并证明了假定的病毒相互作用伙伴（如MARK3）影响免疫反应。我们的结果加速了新药开发计划的评估和优先排序，并重新确定了预防、治疗或减少不良后果的试验目的。通过交互式web服务器（https://omicscience.org/apps/covidpgwas/），可以方便地快速共享和详细查询结果。找到COVID-19的有效治疗方法取决于了解参与SARS-CoV-2感染和宿主反应的蛋白质的遗传调控。在这里，作者确定了与这些蛋白质表达相关的遗传变异，这些数据可能导致发现治疗靶点。
Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/). Finding effective treatments for COVID-19 depends upon understanding genetic regulation of proteins involved in SARS-CoV-2 infection and host response. Here, the authors identify genetic variants linked to expression of such proteins, data which could lead to the discovery of therapeutic targets.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
17.1
作者：
Finan C;Gaulton A;Kruger FA;Lumbers RT;Shah T;Engmann J;Galver L;Kelley R;Karlsson A;Santos R;Overington JP;Hingorani AD;Casas JP
通讯作者：
Casas JP
影响因子：
16.6
作者：
Huang J;Howie B;McCarthy S;Memari Y;Walter K;Min JL;Danecek P;Malerba G;Trabetti E;Zheng HF;UK10K Consortium;Gambaro G;Richards JB;Durbin R;Timpson NJ;Marchini J;Soranzo N
通讯作者：
Soranzo N
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole