Multi-ancestry omic Mendelian randomization revealing putative drug targets of COVID-19 severity
Authors: Zheng Jie , Zhang Yuemiao , Zhao Huiling , Liu Yi , Baird Denis , Karim Mohd Anisul , Ghoussaini Maya , Schwartzentruber Jeremy , Dunham Ian , Elsworth Benjamin , Roberts Katherine , Compton Hannah , Miller-Molloy Felix , Liu Xingzi , Wang Lin , Zhang Hong , Smith George Davey , Gaunt Tom R 
Published: May 2020

Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1,608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritised additional drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions.

MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity only in European ancestry and one protein target, SERPINA1, only showed effect in African ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P=9.96×10−4; OR in Europeans=1.021, P=0.745). One protein, ICAM1, showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P=5.94×10−4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P=0.045). The phenome-wide MR of the prioritised targets on 622 complex traits identified 726 potential causal effects on other diseases, providing information on potential beneficial and adverse effects. Our study prioritised six proteins as potential drug targets for COVID-19 severity. Several of them were targets of existing drug under trials of COVID-19 or related to the immune system. Most of these targets showed different effects in European and African ancestries, which highlights the value of multi-ancestry MR in informing the generalizability of COVID-19 drug targets across ancestries. This study provides a first step towards clinical investigation on COVID-19 and other types of coronaviruses.

Research in context

Evidence before this study

We searched key terms in PUBMED published before Feb 1st 2022, with the terms: (“COVID-19, “coronavirus”) AND (“omics” or “protein” or “transcript”) AND (“Genome-wide association study” or “Mendelian randomization”). We found multiple studies identified targeted genes or proteins associated with COVID-19. However, there is little human genetics evidence support the ancestry-consistent or ancestry-specific genes/proteins associated with COVID-19.

Added value of this study

To our knowledge, this is the first comprehensive genetic study that identified protein targets that showed effect on COVID-19 severity in European and African ancestries. Our study identified one protein, SERPINA1, that showed effects on COVID-19 in African ancestry (OR=0.369, P=9.96×10−4), but not in European ancestry (OR=1.021, P=0.745). In addition, our study identified four additional protein targets, FCRL3, ICAM5, ENTPD5 and OAS1, that showed effect on COVID-19 severity in Europeans. One protein ICAM1 showed suggestive effect in both ancestries. Some of these proteins are related to the immune system and/or are targets of existing drug under trials of COVID-19.

Implications of all available evidence

Our study prioritised six drug targets for COVID-19 severity, five of them showed different effects in European and African ancestries. This suggested that drug targets may have different responses on COVID-19 severity in different ancestries. Our study also highlights the value of intercellular adhesion molecule (ICAM) family in relation with COVID-19 severity in both ancestries.