key: cord-334849-8rblgq9b
authors: LoPresti, Marissa; Beck, David B.; Duggal, Priya; Cummings, Derek A.T.; Solomon, Benjamin D.
title: The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature
date: 2020-08-12
journal: Am J Hum Genet
DOI: 10.1016/j.ajhg.2020.08.007
sha: 
doc_id: 334849
cord_uid: 8rblgq9b

Abstract The SARS-CoV-2 pandemic raises many scientific and clinical questions. These include how host genetic factors affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. We reviewed the literature on host genetic factors related to coronaviruses, with a systematic focus on human studies. We identified 1,832 articles of potential relevance. Seventy-five involved human host genetic factors, of which 35 involved analysis of specific genes or loci; aside from one meta-analysis, all were candidate-driven studies, typically investigating small numbers of research subjects and loci. Three additional case reports were described. Multiple significant loci were identified, including 16 related to susceptibility (of which 7 identified protective alleles), and 16 related to outcomes (of which 3 identified protective alleles). The types of cases and controls used varied considerably; four studies used traditional replication/validation cohorts. Among other studies, 30 involved both human and non-human host genetic factors related to coronavirus, 178 involved study of non-human (animal) host genetic factors related to coronavirus, and 984 involved study of non-genetic host factors related to coronavirus, including involving immunopathogenesis. Previous human studies have been limited by issues that may be less impactful now, including low numbers of eligible participants and limited availability of advanced genomic methods; however, these may raise additional considerations. We outline key genes and loci from animal and human host genetic studies that may bear investigation COVID-19. We also discuss how previous studies may direct current lines of inquiry.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic raises many scientific and clinical questions. One set of questions involves susceptibility and outcomes related to SARS-CoV-2 infection (COVID -19) . Hypotheses suggested to explain observed differences include host sex, age, comorbidities, and genetic factors. 1 As with many complex diseases, the reality for most individuals likely involves a combination of genetic -including viral and host genetics -and non-genetic Relative to other coronaviruses, SARS-CoV-2 has unique biological properties and related clinical impact, but data regarding other coronaviruses may be relevant. Previous studies have been disparate in terms of the virus and species studied, as well as the aims and methods. This has resulted in a rich body of literature that is difficult to efficiently leverage for SARS-CoV-2-related work.

To address this, we aimed to perform a review of the literature to outline previous studies of host genetic factors related to coronaviruses. Our first objective is to systematically encapsulate genes and loci interrogated through these efforts. This can help populate lists of genes that -along with data from related biological studies -may bear scrutiny in the developing and important large-scale host genetic 6 and porcine epidemic diarrhea virus (PEDV)in pigs. 3 The betacoronaviruses consist of four lineages: lineage A (HCoV-OC43 and HCoV-HKU1, as well as coronaviruses affecting other species, such as mouse hepatitis virus (MHV)), lineage B (SARS-CoV-1 and SARS-CoV-2), lineage C (Middle East Respiratory Syndrome (MERS) and many bat coronaviruses), and lineage D (coronaviruses only identified in bats to date). 4 HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63 can result in a variety of presentations, including "common cold" and severe but rarely fatal disease; they are also frequently detected as coinfections with other viruses. 3; 5 There are other rare coronaviruses observed in humans as well as in other species. 2 

Coronaviruses affect many species, from Beluga whales to spotted hyenas to turkeys. Sequelae of disease can range from apparently asymptomatic infections to severe or lethal effects on different organ systems, potentially manifesting as diarrheal, encephalitic, nephritic, respiratory, and other findings. 6 In addition to ecologic studies of wild animals, there are numerous non-observational animal studies of coronaviruses, such as involving ferrets 7 , hamsters, 8 guinea pigs, 9 rats, 10 and non-human primates. 11 Formal host genetic studies have been described for some but not all species. Many studies have simply involved examination of differences in species susceptibility and pathogenesis related to human and non-human coronaviruses, without interrogation of specific variants in a particular species.

Among the host genetic work in animals, the objectives and methods used depend on the species studied. For example, in chickens and pigs, the types of published studies predictably differ from those conducted on experimental mice. That is, while MHV represents a problem for mouse colonies, the rationale of the livestock studies may focus more purely on economic repercussions versus attempts to use a model organism to understand immunopathogenesis. The degree to which results may be J o u r n a l P r e -p r o o f 7 reported through the scientific literature (versus other routes) is also anticipated to differ between these groups. See Figure 2 for a summary of reported interrogated loci in animal studies.

One type of study of host genetic factors involves trying to understand whether and how different species are susceptible to infections. This has several important implications related to human health.

A first implication involves the zoonotic potential of a pathogen. 12 Relevant studies have explored host ranges and reservoirs. For example bat, camel, and human can be infected by MERS, unlike mouse, ferret, hamster, and guinea pigs. SARS-CoV-2 replicates better in ferrets and cats than in dogs, pigs, chickens, and ducks. One explanation involves genetic characteristics of the host receptor for the relevant virus (see Receptor studies section below for further discussion). 13 As a natural reservoir for many coronaviruses, bats have been investigated more extensively than other species outside of laboratory-based animals and livestock. One interesting aspect involves host/pathogen co-evolution. That is, research has included co-evolutionary studies between coronaviruses and the genomes of bat hosts (e.g., by correlating phylogenetic analyses of bat coronaviruses with CYTB in multiple bat species) 14 as well as other genetic/biologic studies related to host genetic factors. These have involved relatively well-characterized genes such as the ACE2 receptor gene with SARS-CoV-1 15 and the DPP4 receptor gene with MERS. 16 Specific residues in the ANPEP receptor gene influence species susceptibility to multiple different coronaviruses. 17 In addition to allowing analyses of host susceptibility, these and similar studies help provide estimates for the timeframe of coronavirus circulation in species and populations. 18 As a second example, camels are an important reservoir of coronaviruses that can infect humans; this became especially relevant in the context of MERS. Several host genetic studies have looked at DPP4 receptor characteristics and species tropism, including comparisons between camels, humans, and other J o u r n a l P r e -p r o o f 8 species. 19 To underscore the importance of considering host factors beyond genetics, many studies have analyzed non-genetic correlations with the spread from camels to humans. Examples in this context include the size of the domesticated camel herds, what the herds were used for (e.g., food or transport), and how active the herds were. 20 In the burgeoning studies of COVID-19 host genetic factors, controlling for these other variables will be challenging and important. However, it is possible that sheer statistical power may be able to address some of these issues. Similar approaches have achieved significant results for other etiologically and medically complex diseases (such as preterm birth), including using some of the same datasets and approaches being proposed for COVID-19 studies. 21 As a final example, palm civets (as well as other species) have been examined related to zoonotic implications of coronavirus disease. Specifically, questions about ACE2 have been described in the context of SARS-CoV-1, and the impact of species-specific variants in this and other genes. 22 This work has emphasized interactions of viral and host genetics. 23 This aspect bears further scrutiny in COVID-19 studies, especially given recent data regarding SARS-CoV-2 genetic changes detected in different areas of the world (e.g., see data from Nextstrain under Web Resources).

In addition to observational studies, experimental approaches have been used to study species susceptibility. Hamsters have been used as model organisms to study coronaviruses, including via standard hamster cell lines as well as other approaches with hamster models. 24 For example, hamsters have been used to study species susceptibility to MHV (related to the Ceacam1 receptor), 25 how alterations of specific Dpp4 amino acids in hamster affect susceptibility to MERS, 19; 26 and the roles of ACE2 and CD209L in SARS-CoV-1 susceptibility. 24 Related to the human implications of this type of work, newer gene editing techniques may be an efficient way to provide experimental validation of specific variants that have been implicated in COVID-19.

J o u r n a l P r e -p r o o f 9 A second, related implication involves identifying experimental animals that mimic human response to the virus (or which can be used to understand the disease in other species). Among other reasons, this can be important for understanding human infection and developing and testing possible treatments; in addition to above-mentioned experimental animals, other animals, including non-human primates have been used to study coronavirus in this way. 27; 28 As usual, these studies have included host receptors as well as genes and mechanisms involved in downstream viral pathogenesis, and have employed a variety of computational and experimental approaches. 13; 29; 30 Beyond receptor studies (see further details below), the site of viral replication appears to vary according to the species and coronavirus. This may be potentially related to tissue-specific receptor expression, such as has been shown in studies of cats and ferrets. 31 This line of reasoning may also be relevant to age-specific differences observed with COVID-19 in humans. 32 That is, one factor that may explain why most children are more mildly affected by COVID-19 is due to age-related differences in ACE2 receptor expression.

In various species, efforts have focused on genes encoding the relevant coronavirus receptor, including effects of viral and host genetic changes and how these may impact the disease process. Among other cell surface determinants, 33 these receptor genes include ACE2 (MIM 30035) for HCoV-NL63, 34 SARS-CoV-1, 35 and SARS-CoV-2, 36 ANPEP (MIM 151530) for HCoV-229, 37 FIPV, 38 CCoV, 39 and TGEV, 40 DPP4 (MIM 102720) for MERS, 41 and Ceacam1 for MHV (see Figure 2 , which summarizes key genes investigated in animal studies on coronaviruses). 42 In animals, significant work has been done related to host genetic factors involving these receptor genes. For example, studies in rats include computational approaches examining receptor characteristics, such as Ace2 in the context of SARS-CoV-1 43 and J o u r n a l P r e -p r o o f 10 experimental approaches that suggest that rats are not susceptible to MERS based on Dpp4 characteristics. 30 In humans (see Tables 1 and S2 and Figures 3 and 4 for details on human studies of these genes, including specific references), studies of specific ACE2 polymorphisms have not shown significant associations with SARS-CoV-1 susceptibility or outcome. CLEC4M (CD209L) (MIM 605872) encodes an alternate receptor with lower viral affinity. There is mixed evidence for an association of susceptibility to SARS-CoV-1 with CLEC4M polymorphisms (tandem repeats). Several studies have used (and are using) existing datasets to explore allele frequencies (such as in ACE2) in various geographic/ancestral populations, with the hypothesis that differences in allele frequencies -as well as observed differences in gene expression -may be one reason for differential impacts of COVID-19 in different parts of the world. 44; 45 In conjunction with population studies, computational functional studies have been performed on identified ACE2 variants. 46 Following up these data through host genetic studies using case and controls will help further examine variants in these and other genes. Validating findings with biological data will also be helpful -for example, a recent study on COVID-19 showed that certain immune mediators, cytokines and chemokines correlate with aspects of disease. 47 Due to today's availability of genomic approaches, and in contrast to the previously published studies (described in Table 1 and Table S2 ), emerging studies on COVID-19 will likely have to consider both rare and common variants in these and other genes, as well as combinatorial models explaining susceptibility and outcomes.

Multiple studies have examined mutant ACE2. Studying the effects of mutant ACE2 on SARS-CoV-1 entry provided evidence that the cytoplasmic tail of ACE2 is not required for SARS-CoV-1 penetration. 48 

Pigs can be infected by transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV), as well as the more recently-identified porcine deltacoronavirus (PDCoV). Like coronavirus disease in chickens, these diseases can affect the food industry, and studies have aimed to address ways to ameliorate disease, such as through vaccines and other methods. 51 Modern gene editing techniques have been studied in this context; these have also garnered recent interest in COVID-19.

In pig studies, variants (both naturally-occurring and experimentally-induced) have been shown to have varying effects on different coronaviruses. For example, aminopeptidase N, encoded by ANPEP (also called APN) was reported as a functional receptor for TGEV and PEDV (as well as HCoV-229E), but multiple models, including CRISPR/Cas9-generated knock-outs, show differences in cellular susceptibility to TGEV and PEDV. 51; 52 In another study, infection by PEDV and TGEV correlated positively with ANPEP expression, but PEDV and TGEV could infect ANPEP-positive and negative enterocytes, with differences observed between viral strains. Overall, the results suggested the presence of an additional receptor. 53 Similar to work on SARS-CoV-1 in humans, variants in these additional receptor gene may be clinically relevant. 24; 54 Building on this type of work, site-specific editing of ANPEP has been raised as a potential means to breed resistant animals. 55 In a similar vein, knock-out of CMAH (hypothesized to affect cellular binding) does not result in immunity to PEDV, but appears to improve outcomes. 56 This line of thinking can be extended to human studies. In COVID-19, the use of splice-switching antisense oligonucleotides has been proposed to affect ACE2 in order to limit SARS-CoV-2 entry. 57 Other 12 modern techniques such as CRISPR have emerged as a powerful tool for many research and a growing number of potential clinical applications. CRISPR has been described as a potential diagnostic and therapeutic tool to test for and combat SARS-CoV-2 infection. 58; 59 CRISPR applications to host cells has also been suggested as a therapeutic avenue. 60 It is likely that additional ethical and biological questions will arise that may echo previous discussions about these approaches in other clinical areas. 61 As with other questions in COVID-19 (e.g., human challenge studies in vaccine trials 62 ), balancing risks and benefits will be critical.

The MHC has been explored in studies of multiple species related to coronavirus, including chickens, 63 domestic cats, 64 and cheetah. 65 As with the human studies summarized below (see also Table 1 and   Table S2 ), the evidence have been mixed and unclear.

Studies of cheetahs present an interesting example related to MHC genes, which may have connections to human COVID-19 studies. Among wild animals, severe population bottlenecks (resulting in reduced genetic diversity) in cheetahs has been used to explain their increased susceptibility to infection by FIPV as well as other infectious diseases. Several such bottlenecks appear to have occurred in cheetah, due to a combination of factors. 66 Among possible explanations for cheetah's coronavirus susceptibility, genetic uniformity of the major histocompatibility complex (MHC) has been proposed. 65 In humans, severe COVID-19 cases have already been reported in peer-reviewed literature 67 (as well as many lay articles), but specific suggestions of associations with consanguinity have not been identified.

However, analyzing such families may be informative, as has been the case for many conditions with genetic underpinnings.

Separate from the above, HLA genes (including MIM 142800, 142830, 142857) have also been studied in humans related to SARS-CoV-1, again with overall mixed evidence (see Tables 1 and S2 and Figures 3 J o u r n a l P r e -p r o o f 13 and 4 for details on human HLA studies, including specific references). HLA alleles that appear to be related to susceptibility and/or outcome of disease have been identified. This mixed evidence may reflect issues with study design, such as sample size and ascertainment. The HLA genes remain a logical target of interest related to COVID-19. 68 As a preface to case/control host genetic studies, a recent report has described peptide-binding affinities between hundreds of HLA Class I and Class II proteins and the proteomes of seven pandemic viruses, including coronaviruses. Similar to human population work on ACE2 and other genes in humans, the HLA alleles have been examined related to peptide-binding affinities. 69 An in silico analysis of viral peptide-MHC class I binding affinity related to HLA genotypes for SARS-CoV-2 peptides, as well as potential cross-protective immunity related to four common human coronaviruses, provides evidence that HLA-B*46:01 may be associated COVID-19 vulnerability, while HLA-B*15:03 may enable cross-protective T-cell based immunity. 70 Correlating these theoretical data with case-control results is a logical next step.

Beyond the HLA genes, other key genes involved in immune processes have been investigated in host genetic studies. We use the extensive mouse studies to illustrate this point.

Differences in the susceptibility of various mouse lines to MHV has been noted for seven decades. 71; 72 This coronavirus remains a challenge for the health of mouse colonies, though relatively recent improvements in animal care practices have been beneficial. 73 Various MHV strains show a range of tissue tropism and host effects on different mouse lines. 74 For example, the JHM strain of MHV causes encephalitis in susceptible animal lines. 75 Unsurprisingly, the majority of host genetic research in mouse models has centered on pathways known to be implicated in viral infection susceptibility. MHV-based mouse studies have used transgenic models to directly test the role of implicated immunologic and related pathways (summarized in Table 2 ). J o u r n a l P r e -p r o o f 14 Work in humans so far has also concentrated on key immune genes (see Tables 1 and S2) ; similar work related to COVID-19 has been proposed. 76 Mouse host genetic studies include investigations of humoral and cellular adaptive immune responses, specific cytokine and immune receptor pathways, viral receptors, complement pathway, apoptosis, autophagy, and tissue repair. These studies have prominently implicated Type I (ɑβ) and II (γ) interferon responses in host response and predominantly protection against MHV infection. However, not all proinflammatory pathways have been shown to be protective. For example, complement activation promotes tissue damage caused by MHV infection, highlighting the complex interplay between the host and virus. These transgenic models have also returned to questions regarding the susceptibility of different strains. 77 In addition to targeted gene disruptions described above, a GWAS using a recombinant inbred mouse panel implicated Trim55, which is involved in vascular cuffing and inflammation in response to SARS-CoV-1. 78 While these studies have provided much better understanding of the disease process, it is not always clear how well the results for one viral strain and mouse line can be extrapolated more broadly. Similar themes emerge in human studies of other conditions. That is, the clinical effects of particular variants may differ from one population to the next, likely due to other, interacting genetic and non-genetic factors. This may make findings in one population difficult to generalize, or may mean that certain genetic variants are most clinically relevant in certain populations. In humans, this issue becomes especially important in clinically-oriented variant analysis. 79 

Multiple lines of evidence suggest a complex relationship between viral and host genetics. Again, mouse studies have focused on this area, as well as exploring other questions regarding susceptibility and pathogenesis. 87 Examinations of different laboratory mouse strains have suggested that multiple loci are involved in host genetic factors related to MHV. 88; 89 Early mouse studies yielded various models, including potential monogenic/Mendelian explanations as well as more complex explanations involving interacting loci. 74; 90; 91 Human studies will be more complex than those on inbred mouse lines. Some of the small candidate-J o u r n a l P r e -p r o o f 16 driven association studies in humans have tried to use combinatorial models, but were likely hampered by multiple issues including the numbers of available cases and controls and the ability to query multiple common and rare variants simultaneously (see Tables 1 and S2 for details). In addition to potentially addressing this complexity with large numbers of participants, elegant approaches have been proposed.

For example, deep investigation of outliers may yield answers that can be further investigated in the general population. 92 These outliers may represent extremes of clinical sequelae, such as those who appear to be unaffected or otherwise young and healthy individuals who are more severely affected than would be anticipated. Specific examples have already been reported in the literature on COVID-19. 93 Another area of interest may involve studying individuals with identified pathogenic or severe variants (e.g., "human knockouts") to determine correlations with COVID-19. Studies of populations that have already been genotyped and extensively studied may be especially powerful.

As described, work in human and animals has explored various host factors related to coronavirus infection. For example, human 94 and animal 10; 95 studies have implicated age as having significant associations with outcomes in coronavirus infections. Currently, age appears to be strongly correlated with COVID-19 outcomes. 96 The overall explanations for this remain unclear, but could involve agerelated gene expression. Sex also appears to be correlated with outcomes. Animal studies identify sex effects in multiple species, such as related to disease severity. 97; 98 Human studies of SARS-CoV-1 and SARS-CoV2 suggest a correlation between sex and certain clinical parameters, perhaps rooted in sexbased or related immunologic differences or gene dosage effects. 94; 99 However, separating biological differences from sex-related cultural practices (e.g., different rates of social distancing) and body habitus (i.e., potential correlations of body mass index with sex separate from strict genetic correlations) may be difficult.

Human host genetic studies on coronavirus have largely been candidate-driven to date (see Tables 1 and   S2 and Figures 3 and 4 for details on human studies, including specific references), though many hypothesis-free studies on COVID-19 are in various phases of completion. As shown in Figures 3 and 4, human studies have examined susceptibility to infection as well as questions regarding various outcomes (some studies investigated both areas). Animal studies on coronaviruses have employed hypothesis-free as well as candidate approaches.

In chickens, the infectious bronchitis virus (IBV) coronavirus can cause disease that affects different organ systems and tissues, such as IBV-associated nephritis. As with other species, inbred status and specific chicken lines have been shown to impact host susceptibility, immune response, and outcomes, and virus/host genetic interactions have been described. 100 Felines can be infected by feline coronavirus (FCoV), which include feline infectious peritonitis (FIPV) and feline enteric coronavirus (FECV). 95 As with other species, cats demonstrate a range of potential effects. In addition to association with traits such as age, sex, and reproductive status, purebred status and loss of heterozygosity has been shown to be associated with the effects of disease. Susceptibility and outcomes also appear to vary between different breeds. 95; 106-108 A small study of feline leukocyte antigen (FLA)-DRB alleles did not show a statistically significant association between FLA-DRB alleles and J o u r n a l P r e -p r o o f 18 FCoV infection outcome. 64 Polymorphisms in IFNG (investigated as FIP can result in decreased interferon-gamma levels) were shown to correlate with plasma interferon-gamma levels and outcomes. 109 Polymorphisms in TNFA and CD209 were also shown to be associated with outcomes in one inbred breed. 110 In addition to candidate studies, several GWAS have been performed in cats. One small study on outcomes in experimentally-induced infections in random-bred cats identified one associated genomic region (which did not harbor any obvious candidate genes). 95 Another small study on an inbred breed identified multiple candidate genes (ELMO1, ERAP1, ERAP2, RRAGA, TNSF10) but none was fully concordant with the FIP disease phenotype. 111 The GWAS approach (which has also been used to study mice, resulting in implication of Trim55, as described above 78 ) raises several important issues. A first issue involves immediate clinical applicability.

That is, GWAS approaches may reveal findings that were not immediately hypothesized to be involved, such as variants in genes other than those known to be involved in viral pathogenesis and immunity. 112 These findings may be statistically significant, but translating results to clinical uses in the near-term may be challenging despite excitement and perhaps incomplete understanding in the lay press. However, these insights may be important for longer-term and equally important purposes, such as related to therapeutic development, or understanding which populations may be overall more or less vulnerable to disease. In other words, pertinent host genetic findings identified in hypothesis-free ways may unearth unexpected findings (beyond receptor, HLA, and well-characterized immune genes) that may yield important next steps to help combat the disease.

A second issue -which has received more recent attention in many genomic studies -involves important secondary information that may be revealed through host genetic research or through genomic testing and studies done for other purposes. Previously, lists of recommended secondary genes have been compiled in general contexts, and recommendations have been made about informing individuals about these findings (prior to the COVID-19 pandemic). With COVID-19, genomic investigators have newly assembled lists of secondary genetic information that may be relevant to the pandemic. These include genes involved in pharmacogenomics, conditions that involve metabolic or thrombotic crises, and cardiopulmonary conditions. 113 Beyond this overarching framework, specific papers have already been published about pharmacogenomic considerations for medications such as anti-IL-6 agents for the treatment of COVID-19 (as well as hydroxychloroquine and azithromycin). 80; 114 Human studies

Details of the human studies are presented in the section on Literature search and sources, and in Table   1 , S2, and Figures 3, 4 , and 5.

Of the 38 human studies on host genetic study factors, 34 (89%) involved SARS-CoV-1, while 4 (11%)

involved SARS-CoV-2. Thirty-five of the 38 studies examined specific genes and loci, as three of the SARS-CoV-2 studies were case reports (two on single families, the other on two patients with a rare immunodeficiency) without specific studies related to host factors. All of the association studies except one were candidate-gene analyses based on genes hypothesized to be important in disease susceptibility or clinical variables/outcome. The exception to date was a meta-analysis of 386 studies on susceptibility to tuberculosis, influenza, respiratory syncytial virus, SARS-CoV-1, and pneumonia. 115 As summarized in Figures 3 and 4 , candidate studies ranged from studies of single variants to studies of over 50 genes selected due to biological plausibility; seven of these studies focused on HLA alleles. Sixteen significant loci related to susceptibility to coronavirus were reported (of which 7 identified protective alleles) (Figure 3 ). Sixteen significant loci related to outcomes or clinical variables were reported (of which 3 identified protective alleles) (Figure 4) . The types of cases and controls used Four studies conducted laboratory-based biological studies in addition to association analyses. Of note, one study related to allele frequencies and expression levels in SARS-CoV-2 focused on specific genes, but used data generated via exome sequencing and SNP-arrays. 44 Large amounts of data generated through these types of genomic assays are currently being analyzed; some results are available on preprint servers and through other data sharing mechanisms.

In addition to the germline variants described in these previous studies, non-germline changes are discussed as possibly pertinent to COVID-19. Correlations between clonal hematopoiesis and COVID-19 mortality have been suggested, 116 as have the potential importance of tumor-based ACE2 genetics and epigenetics. 117

Traditional genome-wide methods have been applied to human viral infections generally, 115 As shown (Table S2 ), the small sample sizes of previous studies may have led to the preponderance of candidate gene studies. The sample sizes may also have precluded significant findings due to limitations of statistical power and the ability to replicate or validate findings. As previous research took place in certain countries and regions ( Figure 5 ), it is possible that the results would not extrapolate to other populations. Finally, candidate approaches can be inherently limited, as non-hypothesized loci may be significantly involved.

Based on announcements about multiple large-scale projects on COVID-19 host genetic factors, as well as the existence of larger genomic datasets that can be mined quickly and new methods that can be used to address biological questions, it is anticipated that considerable efforts -and an unfortunately large pool of research subjects -will yield significant new results quickly.

Though separate from the bulk of the material reviewed here, another area is worthy of brief mention.

These are the rapid and sometimes dramatic changes that have been necessary to manage patients with genetic and related conditions. Just as many genetic researchers have pivoted to address the pandemic, clinical genetic experts have modified their practices to support the patients they serve. The literature already reflects specific guidance and lessons learned for many genetic conditions, such as Charcot-Marie-Tooth, G6PD deficiency, Gaucher disease, inherited arrhthymias, and inborn errors of metabolism (see Table S3 for references for COVID-19 guidance related to these conditions). The information takes into account how the known genetic and biologic underpinnings of disease -as well as related considerations such as pharmacogenomics -should be considered to optimize outcomes. In addition to J o u r n a l P r e -p r o o f 22 these pragmatic guidelines, understanding from studying the impact of COVID-19 on people with these rare diseases may yield insights that can be applied to the population at large, much like unraveling the causes of primary immunodeficiencies can lead to generalizable knowledge about the immune system.

There are multiple limitations to our summaries and analyses. First, it is likely that relevant articles were missed by our search process, and that key findings -including the study of certain genes -were therefore omitted. Along these lines, important findings within identified articles may also have been missed. Due to publication biases, some studies that have been conducted may not have reported relevant data. Second, this analysis focused on DNA-based variants. These DNA-based genetic changes include those studied and identified through association studies as well as genes that were manipulated in experimental approaches, such as via knockout models to understand disease pathogenesis. Related 'omic approaches, such as targeted or broad transcriptomic or proteomic studies, are frequently used to understand important aspects of disease. These approaches can lead to knowledge regarding specific genetic changes. For example, observed transcriptomic changes may enable the identification of important DNA-based variants that explain disease by correlating transcriptomic data with results of DNA sequencing. 119 As another example from proteomics, a recent paper describes the human/SARS-CoV-2 protein-protein interactome, which may be highly relevant for understanding host genetic factors. 120 However, we categorized non-DNA based 'omic approaches separately from DNA-based studies, and did not attempt to comprehensively recapitulate what is known about host reaction to disease. Finally, as the studies varied in many aspects, such as how cases and controls were defined, and which loci were interrogated, we were careful about comparing or combining data between different studies. Table S2 for alleles) J o u r n a l P r e -p r o o f Table S1 . Articles included in the systematic review, with article categorization (based on schema described in Supplemental Methods and Figure 1 ). Table S2 . Details of human studies related to host genetic factors. Table S3 . Supplemental references for specific example papers on genetic conditions and COVID-19.

BDS previously worked for a subsidiary of Opko Health, a company whose subsidiary companies currently perform genetic testing as well as COVID-19 related testing.

This research was supported Table S2 and Supplemental References. Table S2 and Supplemental References. shown in each respective country. Study designs (including related to both cases and controls) differed markedly. Details for each depicted study are given in Table S2 .

J o u r n a l P r e -p r o o f

Viral and host factors related to the clinical outcome of COVID-19

Coronavirus diversity, phylogeny and interspecies jumping

Origin and evolution of pathogenic coronaviruses

Family coronaviridae. Virus taxonomy

Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method

Feline and canine coronaviruses: common genetic and pathobiological features

The SARS-CoV ferret model in an infection-challenge study

Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility

Pathology of guinea pigs experimentally infected with a novel reovirus and coronavirus isolated from SARS patients

Participation of both host and virus factors in induction of severe acute respiratory syndrome (SARS) in F344 rats infected with SARS coronavirus

Replication of SARS coronavirus administered into the respiratory tract of African Green, rhesus and cynomolgus monkeys

Contrasted patterns of variation and evolutionary convergence at the antiviral OAS1 gene in old world primates

Evolutionary relationships between bat coronaviruses and their hosts

Angiotensin-converting enzyme 2 (ACE2) proteins of different bat species confer variable susceptibility to SARS-CoV entry

Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus

Mutational analysis of aminopeptidase N, a receptor for several group 1 coronaviruses, identifies key determinants of viral host range

Interplay between co-divergence and cross-species transmission in the evolutionary history of bat coronaviruses

Host species restriction of Middle East respiratory syndrome coronavirus through its receptor, dipeptidyl peptidase 4

Risk factors for MERS coronavirus infection in dromedary camels in Burkina Faso

Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections

Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human

CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus

The N-terminal region of the murine coronavirus spike glycoprotein is associated with the extended host range of viruses from persistently infected murine cells

Mapping the Specific Amino Acid Residues That Make Hamster DPP4 Functional as a Receptor for Middle East Respiratory Syndrome Coronavirus

Virology: SARS virus infection of cats and ferrets

Exacerbated innate host response to SARS-CoV in aged non-human primates

Infection and Rapid Transmission of SARS-CoV-2 in Ferrets

Inability of rat DPP4 to allow MERS-CoV infection revealed by using a VSV pseudotype bearing truncated MERS-CoV spike protein

Pathology of experimental SARS coronavirus infection in cats and ferrets

Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults

Coronavirus receptor switch explained from the stereochemistry of protein-carbohydrate interactions and a single mutation

Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Human aminopeptidase N is a receptor for human coronavirus 229E

Feline aminopeptidase N serves as a receptor for feline, canine, porcine, and human coronaviruses in serogroup I

Interspecies aminopeptidase-N chimeras reveal species-specific receptor recognition by canine coronavirus, feline infectious peritonitis virus, and transmissible gastroenteritis virus

Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV

Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC

Receptor for mouse hepatitis virus is a member of the carcinoembryonic antigen family of glycoproteins

Characterisation of animal angiotensin-converting enzyme 2 receptors and use of pseudotyped virus to correlate receptor binding with susceptibility of SARS-CoV infection

ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy

Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations

Functional prediction and frequency of coding variants in human ACE2 at binding sites with SARS-CoV-2 spike protein on different populations

Longitudinal COVID-19 profiling associates IL-1Ra and IL-10 with disease severity and RANTES with mild disease

Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted

Truncated human angiotensin converting enzyme 2; a potential inhibitor of SARS-CoV-2 spike glycoprotein and potent COVID-19 therapeutic agent

Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein

Aminopeptidase N is not required for porcine epidemic diarrhea virus cell entry

Resistance to coronavirus infection in amino peptidase N-deficient pigs

Role of Porcine Aminopeptidase N and Sialic Acids in Porcine Coronavirus Infections in Primary Porcine Enterocytes

Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection

Production of porcine aminopeptidase N (pAPN) site-specific edited pigs

Lessening of porcine epidemic diarrhoea virus susceptibility in piglets after editing of the CMP-N-glycolylneuraminic acid hydroxylase gene with CRISPR/Cas9 to nullify N-glycolylneuraminic acid expression

Alternative splicing of ACE2 possibly generates variants that may limit the entry of SARS-CoV-2: a potential therapeutic approach using SSOs

CRISPR-Cas12-based detection of SARS-CoV-2

Development of CRISPR as an Antiviral Strategy to Combat SARS-CoV-2 and Influenza

B-cell engineering: A promising approach towards vaccine development for COVID-19

After the Storm -A Responsible Path for Genome Editing

COVID-19 vaccine development: Time to consider SARS-CoV-2 challenge studies? Vaccine

Retrospective evidence that the MHC (B haplotype) of chickens influences genetic resistance to attenuated infectious bronchitis vaccine strains in chickens

Feline leucocyte antigen class II polymorphism and susceptibility to feline infectious peritonitis

Genetic basis for species vulnerability in the cheetah

Genomic legacy of the African cheetah, Acinonyx jubatus

Case Report: Death Due to Novel Coronavirus Disease (COVID-19) in Three Brothers

Genetic gateways to COVID-19 infection: Implications for risk, severity, and outcomes

Binding affinities of 438 HLA proteins to complete proteomes of seven pandemic viruses and distributions of strongest and weakest HLA peptide binders in populations worldwide

Human leukocyte antigen susceptibility map for SARS-CoV-2

A hepatitis virus of mice

Effect of Cortisone of Genetic Resistance to Mouse Hepatitis Virus in Vivo and in Vitro

Assessing the genetic component of the susceptibility of mice to viral infections

The cellular nature of genetic susceptibility to a virus

In vivo and in vitro models of demyelinating disease: efficiency of virus spread and formation of infectious centers among glial cells is genetically determined by the murine host

COVID-19: Possible Impact of the Genetic Background in IFNL Genes on Disease Outcomes

Acute hepatic failure in IFN-gamma-deficient BALB/c mice after murine coronavirus infection

Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross

Genetic Misdiagnoses and the Potential for Health Disparities

Genetic susceptibility for COVID-19-associated sudden cardiac death in African Americans

Overlapping and distinct molecular determinants dictating the antiviral activities of TRIM56 against flaviviruses and coronavirus

Genetic deficiency and polymorphisms of cyclophilin A reveal its essential role for Human Coronavirus 229E replication

Identification of Residues Controlling Restriction versus Enhancing Activities of IFITM Proteins on Entry of Human Coronaviruses

The nucleolar protein GLTSCR2 is required for efficient viral replication

Interferon induction of IFITM proteins promotes infection by human coronavirus OC43

MAVS-mediated apoptosis and its inhibition by viral proteins

The use of a genetically incompatible combination of host and virus (MHV) for the study of mechanisms of host resistance

Genetic study of mouse sensitivity to MHV3 infection: influence of the H-2 complex

Control of mouse hepatitis virus replication in macrophages by a recessive gene on chromosome 7

Mouse fibroblast mutants selected for survival against mouse hepatitis virus infection show increased resistance to infection and virus-induced cell fusion

A comparative study of resistance to MHV3 infection in genetically homogeneous and heterogeneous mouse populations

A Global Effort to Define the Human Genetics of Protective Immunity to SARS-CoV-2 Infection

Determining Host Factors Contributing to Disease Severity in a Family Cluster of 29 Hospitalized SARS-CoV-2 Patients: Could Genetic Factors Be Relevant in the Clinical Course of COVID-19?

Absence of association between angiotensin converting enzyme polymorphism and development of adult respiratory distress syndrome in patients with severe acute respiratory syndrome: a case control study

The influence of age and genetics on natural resistance to experimentally induced feline infectious peritonitis

Estimates of the severity of coronavirus disease 2019: a model-based analysis

Clinicopathological findings associated with feline infectious peritonitis in Sydney, Australia: 42 cases

CD200 receptor controls sex-specific TLR7 responses to viral infection

COVID-19 pandemic: is a gender-defined dosage effect responsible for the high mortality rate among males? Immunogenetics

Susceptibility of three genetic lines of chicks to infection with a nephropathogenic T strain of avian infectious bronchitis virus

Dramatic differences in the response of macrophages from B2 and B19 MHC-defined haplotypes to interferon gamma and polyinosinic:polycytidylic acid stimulation

Understanding Immune Resistance to Infectious Bronchitis Using Major Histocompatibility Complex Chicken Lines

Genetic differences in susceptibility to a mixture of avian infectious bronchitis virus and Escherichia coli

A genome-wide association study identifies major loci affecting the immune response against infectious bronchitis virus in chicken

Genome-wide association study of antibody level response to NDV and IBV in Jinghai yellow chicken based on SLAF-seq technology

Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus

Prevalence of feline infectious peritonitis in specific cat breeds

The relationship between the feline coronavirus antibody titre and the age, breed, gender and health status of Australian cats

Identification and genotyping of feline infectious peritonitisassociated single nucleotide polymorphisms in the feline interferon-gamma gene

Polymorphisms in the feline TNFA and CD209 genes are associated with the outcome of feline coronavirus infection

Genetic susceptibility to feline infectious peritonitis in Birman cats

Responding to COVID-19 in Istanbul: Perspective from genomic laboratory

Biobanks could identify medically actionable findings relevant for COVID-19 clinical care

The differential response to anti IL-6 treatment in COVID-19: the genetic counterpart

The role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis

Clonal haematopoiesis and COVID-19: A possible deadly liaison

Genetic alteration, RNA expression, and DNA methylation profiling of coronavirus disease 2019 (COVID-19) receptor ACE2 in malignancies: a pan-cancer analysis

Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

MX1 rs2071430 ) 21904596 (AHSG rs2248690) 21958371 (HLA-Cw*1502) 25818534 (CCL2 rs1024611) 25818534 (MBL rs1800450) 25818534 (CCL2 rs1024611 + MBL rs1800450) 26524966

Significant associations with clinical variables/outcomes (includes both protective alleles and risk factors) 15243926 (HLA-B*0703) 15243926 (HLA-DRB1*0301) 15381116 (ACE rs4646994) 15766558 (MX1 rs2071430) 16652313

17570115 ICAM3 rs2304237

CD14 rs2569190

Odds ratios (with confidence intervals, where available) Significant associations with susceptibility (includes both protective alleles and risk factors)