key: cord-0786273-8mavewb5
authors: Liu, P.; Fang, M.; Luo, Y.; Zheng, F.; Jin, Y.; Cheng, F.; Zhu, H.; Jin, X.
title: Rare Variants in Inborn Errors of Immunity Genes Associated with Covid-19 Severity
date: 2022-03-12
journal: nan
DOI: 10.1101/2022.03.09.22270766
sha: 5e2989ce98a04169bfe628cc635b53cb35a5b25d
doc_id: 786273
cord_uid: 8mavewb5

Covid-19 is a contagious disease caused by SARS-CoV-2, a novel severe acute respiratory syndrome coronavirus. Common variants and networks underlying host genetic mechanisms have been extensively studied to identify disease-associated genetic factors. However, there are few studies about the rare variants, typically inborn errors of immunity, in understanding the host genetics behind Covid-19 infection, especially in the Chinese population. To fill this gap, we investigate likely-deleterious missense and high-confidence predicted loss-of-function variants by (a) performing gene- and pathway-level association analyses, (b) examining known genes involved in type I interferon signaling and others previously reported in Covid-19 disease, and (c) identifying candidate genes with accumulating mutations and their potential protein-protein interactions with known genes. Based on our analyses, several putative genes and pathways are uncovered and worth further investigation, for example, genes IL12RB1, TBK1, and TLR3, and pathways Tuberculosis (hsa:05152), Primary Immunodeficiency (hsa:05340), and Influenza A (hsa:05164). These regions generally play an essential role in regulating antiviral innate immunity responses to foreign pathogens and in responding to many inflammatory diseases. We believe that to some extent, as an acute inflammatory disease, Covid-19 is also affected by these inborn errors of immunity. We hope that the identification of these rare genetic factors will provide new insights into the genetic architecture of Covid-19.

Coronavirus 2) (N. Zhu et al. 2020 ) has spread rapidly across the world. By January 50 2022, the ongoing SARS-CoV-2 pandemic has caused more than three hundred and 51 sixty million confirmed cases and more than five million deaths. Host genetic factors 52

have been shown to play critical roles in the disease susceptibility and severity. The 53

Covid-19 Host Genetics Initiative (Covid-19 HGI, https://www.covid19hg.org/) is an 54 international initiative to share the results of host genome-wide associations study 55

(GWAS) meta-analysis of Covid-19 disease. The most recent Covid-19 HGI release 6 56 has reported 24 lead SNPs (P < 5e-8) mapped to nearly 136 genes, such as LZTFL1, 57

ABO, OAS1, DPP9, IFNAR2 (Initiative and Ganna 2021). The estimated heritability of 58

Covid-19 symptoms explained by these common variants was 6.5% (Pairo-Castineira 59 et al. 2021). A twin study with participants from the TwinsUK cohort reported that 31% 60 of phenotypic variance of predicted Covid-19 is due to host genetic factors (Williams 61 et al. 2020) . This leads to a large proportion of unexplained heritability (nearly 25%), 62 commonly referred to as "missing heritability". There is increasing evidence that rare 63 variants also make a major contribution to missing heritability of many complex 64 diseases and traits (Zuk et of Covid-19 but also in the response to vaccination (Smieszek et al. 2021 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 12, 2022. ; missense variants that had potential effects on protein function. The CADD score was 141 annotated by CADD plug-in (Kircher et al. 2014 Finally, we performed an analysis of rare variant accumulation in genes identified 165 by two approaches. The first approach detected genes if there was one variant met the 166 following two conditions: (a) the mutations occurred in only severe patients, and (b) the 167 variant harbored no less than three effect allele counts. We denoted these genes as 168 "individual variant-driven genes". The second approach determined genes if (a) all 169 mutations in the gene occurred in only severe patients, and (b) the total number of 170 mutations in the gene is at least three. We denoted these genes as "all variant-driven 171 genes". We note that, genes identified by the two methods may have some overlaps. 172

Each of the two gene sets was then used for network analysis of protein-protein 173 interactions (PPI) with the above 148 known candidate genes. We used the STRING is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint between non-severe and severe patients and found no significant difference 208 (Supplementary Table S1 ). 209

The gene-level analysis of rare variants was performed between severe and non-severe 211 patients via KGGSeq. We performed the gene-based tests for genes mapped by all rare 212 variants, likely-deleterious missense variants, and HC-pLoF variants, respectively. The 213

gene-based analyses did not identify putative genes that passed the significance 214 threshold of 1e-6 (Supplementary Figure S1A-C) . 215 Furthermore, we leveraged the biological knowledge that sets of genes acting 216 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

In the mutation accumulation analysis, we first investigated whether there were 265 potentially functional mutations unique to severe patients. We filtered in rare variants 266 mutated in only severe patients and with minor allele count (MAC) greater than or equal 267 to three. This resulted in 756 rare variants mapped to 700 genes. Among these variants, 268

we observed a very rare mutation rs777044791 in gene CCR3 at locus 3p21.31 (Table  269 3). The physical distance between rs777044791 and rs11385942 is 0.43MB (GRCh38), 270 a distance typically flanked into the same genomic region (Casto and Feldman 2011). 271

The variant rs11385942 is a common variant located at locus 3p21.31 and was first 272

identified to be associated with respiratory failure due to is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 12, 2022. ;

inflammasome by SARS-CoV-2" (WP4876) (Siu et al. 2019) . In response to viral 299 infection, TRAF3IP3 bridges TRAF3 and MAVS leading to interferon production, 300

indicating its probably strong relationship with Covid-19 disease. 301

We also performed PPI network analysis for the 778 "all variant-driven" genes with 302 the 148 known genes ( Figure 3B) is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 12, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22270766 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 12, 2022. ; is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 12, 2022. ; https://doi.org/10.1101/2022.03.09.22270766 doi: medRxiv preprint

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