caused by CoVs as well as its variable outcome. At present, this question has begun a priority for human genomics. The first extensive systematic review addressing host genetic factors implicated in common respiratory tract infectious diseases is dated after the SARS and MERS outbreaks. Pooled analysis of respiratory infections revealed a significant association with the rs2070874 of the IL4 gene and additional genetic risk factors for tuberculosis. The study implemented a formal assessment of the risk of bias and concluded that almost 95% of eligible studies were affected by a strong risk of bias or confounding [14]. Immune response is the primary arm which should be explored in infectious diseases. Seminal studies on human Mendelian disorders causing deficiencies of the immune response to viruses (reviewed in Casanova JL et al. 2020 [15]) provided the background to investigate the influence of germline genetic variations in other, much more common, sporadic infectious diseases. According to the current paradigm for the complex disorder, the model to explain the genetic susceptibility to infection is not Mendelian—but may be either monogenic or polygenic—and postulates that any single genetic biomarker may be associated with a risk with low to very low effect. CoVs bind their cellular receptors using the homotrimeric spike glycoprotein (S1 subunit and S2 subunit in each spike monomer) on the envelope. Such binding triggers a cascade of events leading to the fusion between the cell and viral membranes for cell entry. X-ray crystallography modelling elucidated the structure of the SARS-CoV-2 receptor-binding motif which binds the human Angiotensin 1 Converting Enzyme 2 (ACE2), demonstrating that the binding mode of the SARS-CoV2 is nearly identical to that observed in previously determined CoV-receptor complex structure [16]. Since it has been demonstrated that the SARS-CoV-2 spike protein interacts with human ACE2 [16, 17], a large number of studies focused on the ACE2 gene to investigate the hypothesis that variability in ACE2 structure and expression is related to different susceptibility to COVID-19 (recently reviewed by Devaux CA et al. [18]). The variability of ACE2, as well as of TMPRSS2 which promotes SARS-CoV-2 cellular entry, was already explored comparing public data from the population of different ancestries, providing the rationale for investigations on patients [19–21]. COVID-19 is a new disease and the current pandemic is incommensurable with other CoV-related clinical conditions. Remarkably, the SARS-CoV-2 infection occurs on a global scale with no influence from acquired immunity, either from vaccines or previous exposures. In turn, this tragic experience is an unprecedented opportunity to explore the genetic determinants of an Di Maria et al. Human Genomics (2020) 14:30 Page 2 of 19 emerging infection. Therefore, the human genetics community should endorse an extraordinary scientific effort to comprehensively investigate the influence of human genetic factors involved in the variability of susceptibility to viral infection and, in particular, in the variability of the clinical manifestations caused by SARS-CoV-2 [15, 22]. We embarked on the present systematic search of genetic association analyses in order to detect all possible hints suggesting the role of the host genome in determining the susceptibility to CoVs infections. We provide here a synthesis of evidence that could be helpful to design and conduct effective studies and, in turn, to find possible healthcare strategies aimed at facing the current COVID-19 pandemic. Methods Design and registration The protocol was published in the PROSPERO repository of systematic reviews (registration number: CRD42020180860). We designed a systematic review process to summarise the results and provide a field synopsis about the host genomic biomarkers associated with COVID-19 and other CoV-associated human syndromes caused by CoVs, and able to explain part of the variability in the relevant phenotype. Secondary key questions, if applicable, regarded the effect size of each associated genomic biomarker and the predictive value of such genomic biomarkers. The protocol was developed according to the guidance of the PRISMA-P extension [23]. The PRISMA framework was applied to design reporting of results [24]. All records retrieved from databases were downloaded locally and managed by using the EndNote™ X8 software facilities. An ad hoc form for data abstraction and synthesis was defined on a worksheet. Eligibility criteria Population: patients affected with COVID-19 and with other severe acute respiratory syndromes sustained by CoVs, with no restriction in a clinical setting. The COVID-19 phenotype was defined extensively to include infection, development of any clinical symptom or sign, grade of severity, specific organ involvement, sequelae or complications. Population studies on healthy individuals were not eligible. Exposure: genomic biomarkers defined according to the European Medicine Agency definition (document EMEA/CHMP/ICH/437986/2006), that is “a measurable DNA and/or RNA characteristic that is an indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other interventions”. This definition